Deuterated tryptamine derivatives and methods of use

ABSTRACT

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with a serotonin 5-HT 2  receptor.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/IB2021/054340 filed May 19, 2021, which claims priority and benefitof U.S. Provisional Application No. 63/026,939 filed May 19, 2020, U.S.Provisional Application No. 63/114,738, filed Nov. 17, 2020 and U.S.Provisional Application No. 63/157,118, filed Mar. 5, 2021. All of theforegoing are incorporated by reference in their entireties.

FIELD

The present disclosure relates generally to chemical compounds and, insome embodiments, to serotonin 5-HT₂ receptor agonists and uses in thetreatment of diseases associated with a 5-HT₂ receptor.

BACKGROUND

There are three, closely related subtypes of serotonin 5-HT₂ receptors(5-HT₂Rs), 5-HT_(2A), 5-HT_(2B), and 5-HT_(2C), and they are primarytargets of classic serotonergic psychedelics, such as lysergic aciddiethylamide (LSD), psilocybin, and 2,5-Dimethoxy-4-bromoamphetamine(DOB). They share approximately 60% transmembrane amino acid homology,which poses a challenge to design molecules with selectivity for onesubtype over the others. Each subtype is expressed in a unique patternin mammals (both in peripheral tissues and in the central nervoussystem), and when stimulated, produces unique biochemical,physiological, and behavioral effects. Activation of 5-HT_(2A)Rs, forexample, predominantly mediates psychedelic effects and elicitsanti-inflammatory effects, whereas activation of 5-HT_(2C)Rs reducesfeeding behavior. Chronic activation of 5-HT_(2B)Rs, however, has beenlinked to valvular heart disease (VHD), a life-threatening adverse event(AE). Furthermore, there are concerns that patients who could benefitfrom a 5-HT_(2A)R pharmacotherapy could be resistant to experiencingpsychedelic effects

Tryptamines are a class of serotonergic psychedelics, and possess veryhigh potencies at serotonin 5-HT₂Rs (in some cases sub-nanomolaraffinities). Certain tryptamines are distinguished from classicpsychedelics and other serotonergic psychedelics by possessingselectivity—in some cases 100-fold—for 5-HT_(2A)Rs over 5-HT_(2B)Rs and5-HT_(2C)Rs.

AEs caused by tryptamines and other serotonergic psychedelics areassociated with ingestion of relatively high doses. Likely owing totheir very high potency at 5-HT_(2A)Rs and 5-HT_(2C)Rs, the active oraldoses of tryptamines are extremely low. For example, 2C—C—NBOMe(2-(4-Chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethan-1-amine)is orally active at doses as low 25 μg, and very strong psychedelicdoses are in the range of 500-700 μg. Thus, misuse or abuse, at orexceeding these doses, can cause visual and auditory hallucinations,agitation, aggressiveness, psychosis, and poisoning has been associatedwith toxicity (e.g., rhabdomyolysis) and fatalities. Furthermore,tryptamines can undergo extensive first-pass metabolism, rendering themorally inactive.

There is a need for serotonin 5-HT_(2A)R agonists that overcome the5-HT_(2B)R problem and the issue of psychedelic effects, as well as aneed to improve their bioavailability and enhance their oral activity.There is a further need for efficient, more convenient, and controllabletryptamine formulations that afford no neurologically toxic (e.g.,psychotomimetic toxic) plasma concentration.

SUMMARY

The present disclosure is based at least in part on the identificationof compounds that modulate serotonin 5-HT₂ receptors and methods ofusing the same to treat diseases associated with a serotonin 5-HT₂receptor. More specifically, the present disclosure provides novelcompounds that permit, for example, once-daily dosing to selectivelyengage 5-HT_(2A)Rs without producing psychedelic effects, and to treatneuropsychiatric and other disorders associated with inflammation.

Without being bound to any particular theory, it is believed that thenovel compounds described herein having selective deuteration, like inthe exocyclic moiety, allow for significant slowing of enzymaticdegradation with improved exposure (i.e., prevention of high drugconcentrations (spiking) observed acutely after administration) andincreased blood-to-brain ratio, resulting in enhanced oralbioavailability. Some compounds described herein confer similar benefitsby selective deuteration of the phenyl ring.

Disclosed herein is a compound according to Formula (III) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, X₁ and X₂ are deuterium.

For some embodiments, Y₁ and Y₂ are hydrogen or deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₄ is hydroxyl and R₂, R₅, R₆, and R₇ are allhydrogen, R₈ and R₉ are not both -CD₃, and R₈ and R₉ are not bothunsubstituted methyl when R₂, R₄, R₅, R₆, and R₇ are all hydrogen.

For some embodiments, when R₄ is hydroxyl, R₉ is hydrogen.

For some embodiments, when R₄ is hydroxyl, R₉ is deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, the compound of formula (III) is a compoundaccording to Formula (III-a), Formula (III-b), Formula (III-c), Formula(III-d), Formula (III-e), Formula (III-f), Formula (III-g), Formula(III-h), Formula (III-i), Formula (III-j), Formula (III-k), Formula(III-l), Formula (III-m), Formula (III-n), Formula (III-o), Formula(III-p), Formula (III-q), Formula (III-r), Formula (III-s), Formula(III-t), Formula (III-u), or Formula (III-v), described below.

Disclosed herein is a compound according to Formula (III-a) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₄ is hydroxyl and R₂, R₅, R₆, and R₇ are allhydrogen, R₈ and R₉ are not both -CD₃, and R₈ and R₉ are not bothunsubstituted methyl when R₂, R₄, R₅, R₆, and R₇ are all hydrogen.

For some embodiments, when R₄ is hydroxyl, R₉ hydrogen or deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-b) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted methyl whenR₂, R₆, and R₇ are all hydrogen.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-c) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-d) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₂, R₆, and R₇ are all hydrogen, R₈ and R₉are not both -CD₃.

For some embodiments, R₉ is hydrogen.

For some embodiments, R₉ is hydrogen or deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-e) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-f) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-g) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-h) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-i) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-j) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-k) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl,

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₄ is hydroxyl and R₂, R₅, R₆, and R₇ are allhydrogen, R₈ and R₉ are not both -CD₃, and R₈ and R₉ are not bothunsubstituted methyl when R₂, R₄, R₅, R₆, and R₇ are all hydrogen.

For some embodiments, when R₄ is hydroxyl, R₉ is hydrogen or deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-l) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted methyl whenR₂, R₆, and R₇ are all hydrogen.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-m) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-n) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₂, R₆, and R₇ are all hydrogen, R₈ and R₉are not both -CD₃.

For some embodiments, R₉ is hydrogen.

For some embodiments, R₉ is deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-o) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-p) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-q) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-r) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen,

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-s) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-t) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-u) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

Disclosed herein is a compound according to Formula (III-v) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, the compound is:

For some embodiments, the compound has the following structure:

For some embodiments, the compound is an agonist of a serotonin 5-HT₂receptor.

For some embodiments, the compound can be agonists of a serotonin5-HT_(2A) receptor.

Also disclosed herein is a pharmaceutical composition comprising acompound as disclosed herein and a pharmaceutically acceptable vehicle.

Also disclosed herein is a method of treating a subject with a diseaseor disorder comprising administering to the subject a therapeuticallyeffective amount of a compound as disclosed herein.

Also disclosed herein is a method of treating a subject with a diseaseor disorder comprising administering to the subject a therapeuticallyeffective amount of a compound as disclosed herein.

Also disclosed herein is a method of treating a subject with a diseaseor disorder associated with a serotonin 5-HT₂ receptor comprisingadministering to the subject a therapeutically effective amount of acompound as disclosed herein. In some embodiments, the compound has thefollowing structure:

In some embodiments, the disease or disorder may include central nervoussystem (CNS) disorders, for example, post-traumatic stress disorder(PTSD), major depressive disorder (MDD), treatment-resistant depression(TRD), suicidal ideation, suicidal behavior, major depressive disorderwith suicidal ideation or suicidal behavior, nonsuicidal self-injurydisorder (NSSID), bipolar and related disorders (including but notlimited to bipolar I disorder, bipolar II disorder, cyclothymicdisorder), obsessive-compulsive disorder (OCD), generalized anxietydisorder (GAD), social anxiety disorder, substance use disorders(including but not limited to alcohol use disorder, opioid use disorder,amphetamine use disorder, nicotine use disorder, and cocaine usedisorder), anorexia nervosa, bulimia nervosa, Alzheimer's disease,cluster headache and migraine, attention deficit hyperactivity disorder(ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluencydisorder, major neurocognitive disorder, mild neurocognitive disorder,sexual dysfunction, and obesity. In some embodiments, the disease ordisorder is alcohol use disorder. In some embodiments, the disease ordisorder may include conditions of the autonomic nervous system (ANS).In some embodiments, the disease or disorder may include pulmonarydisorders (e.g., asthma and chronic obstructive pulmonary disorder(COPD). In some embodiments, the disease or disorder may includecardiovascular disorders (e.g., atherosclerosis).

Also disclosed is a method of treating a subject with alcohol usedisorder associated with a serotonin 5-HT₂ receptor comprisingadministering to the subject a therapeutically effective amount of acompound having the following structure:

Also disclosed herein is a single-layer orally administered tabletcomposition comprising a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, and a polymer. In someembodiments, the compound has the following structure:

In some embodiments, the composition is adapted for maximum sustainedrelease.

In some embodiments, the tablet composition comprises a combination of(i) a water-insoluble neutrally charged non-ionic matrix; (ii) a polymercarrying one or more negatively charged groups; and (iii) a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof.

In some embodiments, the non-ionic matrix is selected fromcellulose-based polymers, alone or enhanced by mixing with componentssuch as starches; waxes; neutral gums; polymethacrylates; PVA; PVA/PVPblends; or mixtures thereof.

In some embodiments, the cellulose-based polymer is hydroxypropylmethylcellulose (HPMC).

In some embodiments, the polymer carrying one or more negatively chargedgroups is polyacrylic acid, polylactic acid, polyglycolic acid,polymethacrylate carboxylates, cation-exchange resins, clays, zeolites,hyaluronic acid, anionic gums, salts thereof, or mixtures thereof.

In some embodiments, the anionic gum is a naturally occurring material,a semi-synthetic material, or combinations thereof.

In some embodiments, the naturally occurring material is alginic acid,pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, gumkaraya, guar gum, gum tragacanth, or combinations thereof.

In some embodiments, the semi-synthetic material iscarboxymethyl-chitin, cellulose gum, or combinations thereof.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, for the treatment of pain.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, for the treatment of braininjury.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, for the treatment ofdepression.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, for use in treating a diseaseor disorder associated with a serotonin 5-HT₂ receptor.

For some embodiments, the disease or disorder is selected from the groupconsisting of central nervous system (CNS) disorders, including majordepressive disorder (MDD), major depressive disorder (MDD) with suicidalideation or suicidal behavior, suicidal ideation, suicidal behavior,non-suicidal self-injury disorder (NSSID), treatment-resistantdepression (TRD), post-traumatic stress disorder (PTSD), bipolar andrelated disorders including bipolar I disorder, bipolar II disorder,cyclothymic disorder, obsessive-compulsive disorder (OCD), generalizedanxiety disorder (GAD), social anxiety disorder, substance use disordersincluding alcohol use disorder, opioid use disorder, amphetamine usedisorder, nicotine use disorder, and cocaine use disorder, anorexianervosa, bulimia nervosa, Alzheimer's disease, cluster headache andmigraine, attention deficit hyperactivity disorder (ADHD), pain andneuropathic pain, aphantasia, childhood-onset fluency disorder, majorneurocognitive disorder, mild neurocognitive disorder, sexualdysfunction, chronic fatigue syndrome, Lyme Disease, and obesity, orcombinations thereof. In some embodiments, the disease or disorder isalcohol use disorder.

For some embodiments, the disease or disorder includes conditions of theautonomic nervous system (ANS).

For some embodiments, the disease or disorder includes pulmonarydisorders including asthma and chronic obstructive pulmonary disorder(COPD).

For some embodiments, the disease or disorder includes cardiovasculardisorders including atherosclerosis.

In some embodiments, the composition achieves a combined concentrationof a tryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, andpsilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, in plasma in the range of10-500 (e.g., about 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350,400, 450, 500 or more ng/ml (or any range between about 10 and about 500ng/ml, e.g., about 100 to about 300 ng/ml, about 250 to about 450 ng/ml,or about 50 to about 400 ng/ml), and maintains this concentration forduration of the release period.

In some embodiments, the polymer comprises one or more negativelycharged groups.

Also disclosed herein is a tablet composition formulated for oraladministration comprising: a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, and a polymer. Insome embodiments, the compound has the following structure:

In some embodiments, the polymer comprises one or more negativelycharged groups.

In some embodiments, the polymer comprises one or more acid groups.

In some embodiments, the polymer comprises a water-insoluble neutrallycharged non-ionic matrix.

In some embodiments, the non-ionic matrix is selected fromcellulose-based polymers, alone or enhanced by mixing with componentssuch as starches; waxes; neutral gums; polymethacrylates; PVA; PVA/PVPblends; or mixtures thereof.

In some embodiments, the cellulose-based polymer is hydroxypropylmethylcellulose (HPMC).

Also described herein is a kit for the treatment of a subjectcomprising 1) a single-layer orally administered tablet composition asdisclosed herein, and 2) instructions for use in the treatment of pain.

Also described herein is a kit for the treatment of a subjectcomprising 1) a single-layer orally administered tablet composition asdisclosed herein, and 2) instructions for use in the treatment of braininjury.

Also described herein is a kit for the treatment of a subjectcomprising 1) a single-layer orally administered tablet composition asdisclosed herein, and 2) instructions for use in the treatment ofdepression.

Also described herein is a kit for the treatment of a subjectcomprising 1) a single-layer orally administered tablet composition asdisclosed herein, and 2) instructions for use in the treatment of adisease or disorder associated with a serotonin 5-HT₂ receptor.

DETAILED DESCRIPTION

In the following detailed description of the embodiments of the instantdisclosure, numerous specific details are set forth in order to providea thorough understanding of the disclosed embodiments. However, it willbe obvious to one skilled in the art that the embodiments of thisdisclosure may be practiced without these specific details. In otherinstances, well known methods, procedures, components, and circuits havenot been described in detail so as not to unnecessarily obscure aspectsof the embodiments of the instant disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this disclosure belongs.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way ofexample, linear and branched hydrocarbyl groups such as methyl (CH₃—),ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—), n-butyl(CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—), sec-butyl ((CH₃)(CH₃CH₂)CH—),t-butyl ((CH₃)₃C—), n-pentyl (CH₃CH₂CH₂CH₂CH₂—), and neopentyl((CH₃)₃CCH₂—).

The term “substituted alkyl” refers to an alkyl group as defined hereinwherein one or more carbon atoms in the alkyl chain have been optionallyreplaced with a heteroatom such as —O—, —N—, —S—, —S(O)_(n)— (where n is0 to 2), —NR— (where R is hydrogen or alkyl) and having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, and —NR^(a)R^(b), wherein R′ and R″ may be the same ordifferent and are chosen from hydrogen, optionally substituted alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl andheterocyclic.

“Alkylene” refers to divalent aliphatic hydrocarbyl groups having from 1to 6, including, for example, 1 to 3 carbon atoms that are eitherstraight-chained or branched, and which are optionally interrupted withone or more groups selected from —O—, —NR¹⁰—, —NR¹⁰C(O)—, —C(O)NR¹⁰— andthe like. This term includes, by way of example, methylene (—CH₂—),ethylene (—CH₂CH₂—), n-propylene (—CH₂CH₂CH₂—), iso-propylene(—CH₂CH(CH₃)—), (—C(CH₃)₂CH₂CH₂—), (—C(CH₃)₂CH₂C(O)—),(—C(CH₃)₂CH₂C(O)NH—), (—CH(CH₃)CH₂—), and the like.

“Substituted alkylene” refers to an alkylene group having from 1 to 3hydrogens replaced with substituents as described for carbons in thedefinition of “substituted” below.

The term “alkane” refers to alkyl group and alkylene group, as definedherein.

The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl”refers to the groups R′NHR″— where R′ is alkyl group as defined hereinand R″ is alkylene, alkenylene or alkynylene group as defined herein.

The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and-substituted alkylene-aryl where alkylene, substituted alkylene and arylare defined herein.

“Alkoxy” refers to the group —O-alkyl, wherein alkyl is as definedherein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. Theterm “alkoxy” also refers to the groups alkenyl-O—, cycloalkyl-O—,cycloalkenyl-O—, and alkynyl-O—, where alkenyl, cycloalkyl,cycloalkenyl, and alkynyl are as defined herein.

The term “substituted alkoxy” refers to the groups substituted alkyl-O—,substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein.

The term “alkoxyamino” refers to the group —NH-alkoxy, wherein alkoxy isdefined herein.

The term “haloalkoxy” refers to the groups alkyl-O— wherein one or morehydrogen atoms on the alkyl group have been substituted with a halogroup and include, by way of examples, groups such as trifluoromethoxy,and the like.

The term “haloalkyl” refers to a substituted alkyl group as describedabove, wherein one or more hydrogen atoms on the alkyl group have beensubstituted with a halo group. Examples of such groups include, withoutlimitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl,trifluoroethyl and the like.

The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.

The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.

“Alkenyl” refers to straight chain or branched hydrocarbyl groups havingfrom 2 to 6 carbon atoms, for example 2 to 4 carbon atoms and having atleast 1, for example from 1 to 2 sites of double bond unsaturation. Thisterm includes, by way of example, bi-vinyl, allyl, and but-3-en-1-yl.Included within this term are the cis and trans isomers or mixtures ofthese isomers.

The term “substituted alkenyl” refers to an alkenyl group as definedherein having from 1 to 5 substituents, or from 1 to 3 substituents,selected from alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxy amino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms, for example, 2 to 3 carbon atoms andhaving at least 1 and for example, from 1 to 2 sites of triple bondunsaturation. Examples of such alkynyl groups include acetylenyl(—C≡CH), and propargyl (—CH₂C≡CH).

The term “substituted alkynyl” refers to an alkynyl group as definedherein having from 1 to 5 substituents, or from 1 to 3 substituents,selected from alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, and —SO₂-heteroaryl.

“Alkynyloxy” refers to the group —O-alkynyl, wherein alkynyl is asdefined herein. Alkynyloxy includes, by way of example, ethynyloxy,propynyloxy, and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclyl-C(O)—, and substitutedheterocyclyl-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein. For example, acylincludes the “acetyl” group CH₃C(O)

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O)substitutedalkyl, NR²⁰C(O)cycloalkyl, —NR²⁰C(O)substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O)substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O)substituted aryl,—NR²⁰C(O)heteroaryl, —NR²⁰C(O)substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclic, whereinR²⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminocarbonyl” or the term “aminoacyl” refers to the group—C(O)NR²¹R²², wherein R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the group —NR²¹C(O)NR²²R²³ where R²¹,R²², and R²³ are independently selected from hydrogen, alkyl, aryl orcycloalkyl, or where two R groups are joined to form a heterocyclylgroup.

The term “alkoxycarbonylamino” refers to the group —NRC(O)OR where eachR is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, andheterocyclyl are as defined herein.

The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclyl-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclyl are as defined herein.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and where R²¹ and R²²are optionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group and alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 18 carbon atoms having a single ring (such as is present in aphenyl group) or a ring system having multiple condensed rings (examplesof such aromatic ring systems include naphthyl, anthryl and indanyl)which condensed rings may or may not be aromatic, provided that thepoint of attachment is through an atom of an aromatic ring. This termincludes, by way of example, phenyl and naphthyl. Unless otherwiseconstrained by the definition for the aryl substituent, such aryl groupscan optionally be substituted with from 1 to 5 substituents, or from 1to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.

“Aryloxy” refers to the group —O-aryl, wherein aryl is as definedherein, including, by way of example, phenoxy, naphthoxy, and the like,including optionally substituted aryl groups as also defined herein.

“Amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that atleast one R is not hydrogen.

The term “azido” refers to the group —N₃.

“Carboxyl,” “carboxy” or “carboxylate” refers to —CO₂H or salts thereof.

“Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or“carboxylalkyl” refers to the groups —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-aryl, —C(O)O-substituted aryl,—C(O)O-cycloalkyl, —C(O)O-substituted cycloalkyl, —C(O)O-cycloalkenyl,—C(O)O-substituted cycloalkenyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic,wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“(Carboxyl ester)oxy” or “carbonate” refers to the groups —O—C(O)O—alkyl, —O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl,—O—C(O)O-substituted alkenyl, —O—C(O)O— alkynyl, —O—C(O)O-substitutedalkynyl, —O—C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O— cycloalkyl,—O—C(O)O-substituted cycloalkyl, —O—C(O)O-cycloalkenyl,—O—C(O)O-substituted cycloalkenyl, —O—C(O)O-heteroaryl,—O—C(O)O-substituted heteroaryl, —O—C(O)O-heterocyclic, and—O—C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Cyano” or “nitrile” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of suitable cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyland the like. Such cycloalkyl groups include, by way of example, singlering structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, and the like, or multiple ring structures such asadamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO— substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to10 carbon atoms having single or multiple rings and having at least onedouble bond and for example, from 1 to 2 double bonds.

The term “substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents, or from 1 to 3 substituents, selected fromalkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxy amino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

“Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10carbon atoms having single or multiple rings and having at least onetriple bond.

“Cycloalkoxy” refers to —O-cycloalkyl.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms,such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected fromthe group consisting of oxygen, nitrogen, and sulfur within the ring.Such heteroaryl groups can have a single ring (such as, pyridinyl,imidazolyl or furyl) or multiple condensed rings in a ring system (forexample as in groups such as, indolizinyl, quinolinyl, benzofuran,benzimidazolyl or benzothienyl), wherein at least one ring within thering system is aromatic and at least one ring within the ring system isaromatic, provided that the point of attachment is through an atom of anaromatic ring. In certain embodiments, the nitrogen and/or sulfur ringatom(s) of the heteroaryl group are optionally oxidized to provide forthe N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes,by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, andfuranyl. Unless otherwise constrained by the definition for theheteroaryl substituent, such heteroaryl groups can be optionallysubstituted with 1 to 5 substituents, or from 1 to 3 substituents,selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkoxy, substituted alkenyl, substituted alkynyl, substitutedcycloalkyl, substituted cycloalkenyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl, —SO—substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl, andtrihalomethyl.

The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl wherealkylene and heteroaryl are defined herein. This term includes, by wayof example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

“Heteroaryloxy” refers to —O-heteroaryl.

“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl”refer to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, and having from 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting ofnitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or moreof the rings can be cycloalkyl, aryl, or heteroaryl, provided that thepoint of attachment is through the non-aromatic ring. In certainembodiments, the nitrogen and/or sulfur atom(s) of the heterocyclicgroup are optionally oxidized to provide for the N-oxide, —S(O)—, or—SO₂— moieties.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, or from 1 to 3 substituents, selected from alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl, and fused heterocycle.

“Heterocyclyloxy” refers to the group —O-heterocyclyl.

The term “heterocyclylthio” refers to the group heterocyclic-S—.

The term “heterocyclene” refers to the diradical group formed from aheterocycle, as defined herein.

The term “hydroxy amino” refers to the group —NHOH.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O).

“Sulfonyl” refers to the group SO₂-alkyl, SO₂-substituted alkyl,SO₂-alkenyl, SO₂-substituted alkenyl, SO₂-cycloalkyl, SO₂-substitutedcycloalkyl, SO₂-cycloalkenyl, SO₂-substituted cylcoalkenyl, SO₂-aryl,SO₂-substituted aryl, SO₂-heteroaryl, SO₂-substituted heteroaryl,SO₂-heterocyclic, and SO₂-substituted heterocyclic, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. Sulfonyl includes, by way of example, methyl-SO₂—, phenyl-SO₂—,and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, OSO₂-substituted alkyl,OSO₂-alkenyl, OSO₂-substituted alkenyl, OSO₂-cycloalkyl,OSO₂-substituted cycloalkyl, OSO₂-cycloalkenyl, OSO₂-substitutedcylcoalkenyl, OSO₂-aryl, OSO₂-substituted aryl, OSO₂-heteroaryl,OSO₂-substituted heteroaryl, OSO₂-heterocyclic, and OSO₂ substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

The term “aminocarbonyloxy” refers to the group —OC(O)NRR where each Ris independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl,or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioxo” or the term “thioketo” refers to the atom (═S).

“Alkylthio” or the term “thioalkoxy” refers to the group —S-alkyl,wherein alkyl is as defined herein. In certain embodiments, sulfur maybe oxidized to —S(O)—. The sulfoxide may exist as one or morestereoisomers.

The term “substituted thioalkoxy” refers to the group —S-substitutedalkyl.

The term “thioaryloxy” refers to the group aryl-S— wherein the arylgroup is as defined herein including optionally substituted aryl groupsalso defined herein.

The term “thioheteroaryloxy” refers to the group heteroaryl-S— whereinthe heteroaryl group is as defined herein including optionallysubstituted aryl groups as also defined herein.

The term “thioheterocyclooxy” refers to the group heterocyclyl-S—wherein the heterocyclyl group is as defined herein including optionallysubstituted heterocyclyl groups as also defined herein.

In addition to the disclosure herein, the term “substituted,” when usedto modify a specified group or radical, can also mean that one or morehydrogen atoms of the specified group or radical are each, independentlyof one another, replaced with the same or different substituent groupsas defined below.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for substituting for one or more hydrogens(any two hydrogens on a single carbon can be replaced with ═O, ═NR⁷⁰,═N—OR⁷⁰, ═N₂ or ═S) on saturated carbon atoms in the specified group orradical are, unless otherwise specified, —R⁶⁰, halo, ═O, —OR⁷⁰, —SR⁷⁰,—NR⁸⁰R⁸⁰, trihalomethyl, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰,—SO₂O-M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂,—P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰,—C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)O⁻M⁺, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰ isselected from the group consisting of optionally substituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl, each R⁷⁰ is independentlyhydrogen or R⁶⁰; each R⁸⁰ is independently R⁷⁰ or alternatively, twoR⁸⁰'s, taken together with the nitrogen atom to which they are bonded,form a 5-, 6- or 7-membered heterocycloalkyl which may optionallyinclude from 1 to 4 of the same or different additional heteroatomsselected from the group consisting of O, N and S, of which N may have —Hor C₁-C₃ alkyl substitution; and each M⁺ is a counter ion with a netsingle positive charge. Each M⁺ may independently be, for example, analkali ion, such as K⁺, Na⁺, Li⁺; an ammonium ion, such as ⁺N(R⁶⁰)₄; oran alkaline earth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or[Ba²⁺]_(0.5) (“subscript 0.5 means that one of the counter ions for suchdivalent alkali earth ions can be an ionized form of a compound of thedisclosure and the other a typical counter ion such as chloride, or twoionized compounds disclosed herein can serve as counter ions for suchdivalent alkali earth ions, or a doubly ionized compound of thedisclosure can serve as the counter ion for such divalent alkali earthions). As specific examples, —NR⁸⁰R⁸⁰ meant to include —NH₂, —NH-alkyl,N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl andN-morpholinyl.

In addition to the disclosure herein, substituent groups for hydrogenson unsaturated carbon atoms in “substituted” alkene, alkyne, aryl andheteroaryl groups are, unless otherwise specified, —R⁶⁰, halo, —O⁻M⁺,—OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺,—OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰,—C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰,—OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined, provided that in case of substituted alkene or alkyne, thesubstituents are not —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, or —S⁻M⁺.

In addition to the groups disclosed with respect to the individual termsherein, substituent groups for hydrogens on nitrogen atoms in“substituted” heteroalkyl and cycloheteroalkyl groups are, unlessotherwise specified, —R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰,trihalomethyl, —CF₃, —CN, —NO, —NO₂, —S(O)₂R⁷⁰, —S(O)₂O⁻M⁺, —S(O)₂OR⁷⁰,—OS(O)₂R⁷⁰, —OS(O)₂O⁻M⁺, —OS(O)₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰,—C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰,—OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

In addition to the disclosure herein, in a certain embodiment, a groupthat is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3substituents, 1 or 2 substituents, or 1 substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group, etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups specifically contemplated herein are limited to substitutedaryl-(substituted aryl)-substituted aryl.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

As to any of the groups disclosed herein which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, the subjectcompounds include all stereochemical isomers arising from thesubstitution of these compounds.

The term “pharmaceutically acceptable salt” means a salt which isacceptable for administration to a patient, such as a mammal (salts withcounterions having acceptable mammalian safety for a given dosageregime). Such salts can be derived from pharmaceutically acceptableinorganic or organic bases and from pharmaceutically acceptableinorganic or organic acids. “Pharmaceutically acceptable salt” refers topharmaceutically acceptable salts of a compound, which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, formate, tartrate, besylate,mesylate, acetate, maleate, oxalate, and the like.

The term “salt thereof” means a compound formed when a proton of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Where applicable, the salt is a pharmaceutically acceptablesalt, although this is not required for salts of intermediate compoundsthat are not intended for administration to a patient. By way ofexample, salts of the present compounds include those wherein thecompound is protonated by an inorganic or organic acid to form a cation,with the conjugate base of the inorganic or organic acid as the anioniccomponent of the salt.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.When the solvent is water, the solvate formed is a hydrate.

“Stereoisomer” and “stereoisomers” refer to compounds that have sameatomic connectivity but different atomic arrangement in space.Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers,and diastereomers.

“Tautomer” refers to alternate forms of a molecule that differ only inelectronic bonding of atoms and/or in the position of a proton, such asenol-keto and imine-enamine tautomers, or the tautomeric forms ofheteroaryl groups containing a —N═C(H)—NH— ring atom arrangement, suchas pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Aperson of ordinary skill in the art would recognize that othertautomeric ring atom arrangements are possible.

It will be appreciated that the term “or a salt or solvate orstereoisomer thereof” is intended to include all permutations of salts,solvates and stereoisomers, such as a solvate of a pharmaceuticallyacceptable salt of a stereoisomer of subject compound.

As used herein, the language “maximum sustained release” describes therelease window for certain formulations of the present disclosureformulated to increase the release period to a maximum value, which isultimately limited by the time the gastrointestinal tract naturallyexcretes all drugs with food.

The language “tamper resistance” is art-recognized to describe aspectsof a drug formulation that make it more difficult to use the formulationto abuse the drug moiety of the formulation through extraction forintravenous use, or crushing for freebase use; and therefore reduce therisk for abuse of the drug.

As used herein, the term “steady” describes the stable or steady-statelevel of a molecule concentration, e.g., concentration of any compounddescribed herein.

As used herein, the term “composition” is equivalent to the term“formulation.”

As used herein, the language “administration event” describes theadministration of a subject a given dose, in the form of one or morepills within a short window of time, e.g., less than 10 minutes.

As used herein, the language “release period” describes the time windowin which any compound described herein is released from the matrix toafford plasma concentrations of compounds described herein. The starttime of the release period is defined from the point of oraladministration to a subject, which is considered nearly equivalent toentry into the stomach, and initial dissolution by gastric enzymes andacid. The end time of the release period is defined as the point whenthe entire loaded drug is released. In embodiments, the release periodcan be greater than about 4 hours, 8 hours, 12 hours, 16 hours, or 20hours, greater than or equal to about 24 hours, 28 hours, 32 hours, 36hours, or 48 hours, or less than about 48 hours, 36 hours, 4 hours orless, 3 hours or less, 2 hours or less, or 1 hour or less.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition in a patient, such as amammal (particularly a human) that includes: ameliorating the disease ormedical condition, such as, eliminating or causing regression of thedisease or medical condition in a patient; suppressing the disease ormedical condition, for example by, slowing or arresting the developmentof the disease or medical condition in a patient; or alleviating asymptom of the disease or medical condition in a patient. In anembodiment, prophylactic treatment can result in preventing the diseaseor medical condition from occurring, in a subject.

“Patient” refers to human and non-human subjects, especially mammaliansubjects.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease, disorder, or condition, or of one ormore symptoms thereof. The terms encompass the inhibition or reductionof a symptom of the particular disease, disorder, or condition. Subjectswith familial history of a disease, disorder, or condition, inparticular, are candidates for preventive regimens in certainembodiments. In addition, subjects who have a history of recurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease, disorder, or condition,or of one or more symptoms thereof. Often, the beneficial effects that asubject derives from a prophylactic and/or therapeutic agent do notresult in a cure of the disease, disorder, or condition. In this regard,the term “managing” encompasses treating a subject who had suffered fromthe particular disease, disorder, or condition in an attempt to preventor minimize the recurrence of the disease, disorder, or condition.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease or one or more of its symptoms and/or to prevent theoccurrence of the disease or disorder.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of an active agent, is an amount sufficient to preventa disease, disorder, or condition, or prevent its recurrence. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

The language “neurologically toxic spikes” is used herein to describespikes in concentration of any compound described herein that wouldproduce side-effects of sedation or psychotomimetic effects, e.g.,hallucination, dizziness, and nausea; which can not only have immediaterepercussions, but also effect treatment compliance. In particular, sideeffects may become more pronounced at blood concentration levels aboveabout 300 ng/L (e.g. above about 300, 400, 500, 600 or more ng/L).

As used herein, and unless otherwise specified, a “neuropsychiatricdisease or disorder” is a behavioral or psychological problem associatedwith a known neurological condition, and typically defined as a clusterof symptoms that co-exist. Examples of neuropsychiatric disordersinclude, but are not limited to, schizophrenia, cognitive deficits inschizophrenia, attention deficit disorder, attention deficithyperactivity disorder, bipolar and manic disorders, depression or anycombinations thereof.

“Inflammatory conditions” or “inflammatory disease,” as used herein,refers broadly to chronic or acute inflammatory diseases. Inflammatoryconditions and inflammatory diseases, include but are not limited torheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis,psoriatic arthritis) spondyloarthropathies (e.g., ankylosingspondylitis, reactive arthritis, Reiter's syndrome), crystalarthropathies (e.g., gout, pseudogout, calcium pyrophosphate depositiondisease), multiple sclerosis, Lyme disease, polymyalgia rheumatica;connective tissue diseases (e.g., systemic lupus erythematosus, systemicsclerosis, polymyositis, dermatomyositis, Sjogren's syndrome);vasculitides (e.g., polyarteritis nodosa, Wegener's granulomatosis,Churg-Strauss syndrome); inflammatory conditions including consequencesof trauma or ischaemia, sarcoidosis; vascular diseases includingatherosclerotic vascular disease, atherosclerosis, and vascularocclusive disease (e.g., atherosclerosis, ischaemic heart disease,myocardial infarction, stroke, peripheral vascular disease), andvascular stent restenosis; ocular diseases including uveitis, cornealdisease, iritis, iridocyclitis, and cataracts.

As used herein, the term “and/or” includes any and all combinations ofone or more of the associated listed items. As used in the descriptionherein and throughout the claims that follow, the meaning of “a”, “an”,and “the” includes plural reference as well as the singular referenceunless the context clearly dictates otherwise. The term “about” inassociation with a numerical value means that the value varies up ordown by 5%. For example, for a value of about 100, means 95 to 105 (orany value between 95 and 105).

Compounds

Disclosed herein is a compound according to Formula (I) or an opticallypure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein X₁ and X₂ are deuterium and Y₁ and Y₂ are deuterium.

For some embodiments, R is

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl, under theproviso that when R₄ is hydroxyl, R₈ and R₉ are not both -CD₃.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl, under theproviso that when R₄ is hydroxyl, R₉ is hydrogen or deuterium.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl, under theproviso that when R₄ is hydroxyl, R₉ is not an unsubstituted orsubstituted alkyl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (I-a) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein X₁ and X₂ are deuterium and Y₁ and Y₂ aredeuterium.

For some embodiments, R is

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl, under the proviso that when R₄ is hydroxyl,R₈ and R₉ are not both -CD₃.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl, under the proviso that when R₄ is hydroxyl,R₉ is hydrogen or deuterium.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl, under the proviso that when R₄ is hydroxyl,R₉ is not an unsubstituted or substituted alkyl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (I-b) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein X₁ and X₂ are deuterium and Y₁ and Y₂ aredeuterium.

For some embodiments, R is

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl, under theproviso that when R₄ is hydroxyl, R₈ and R₉ are not both -CD₃.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl, under theproviso that when R₄ is hydroxyl, R₉ is hydrogen or deuterium.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl, under theproviso that when R₄ is hydroxyl, R₉ is not unsubstituted or substitutedalkyl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (I-c) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (I-d) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (I-e) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl, under the proviso that R₈ and R₉ are not both-CD₃.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (I-f) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl, under theproviso that R₈ and R₉ are not both -CD₃.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (I-g) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (I-h) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (I-i) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (I-j) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (I-k) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (II) or an opticallypure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein X₁ and X₂ are deuterium, and Y₁ and Y₂ are hydrogen.

For some embodiments, R is

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (II-a) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein X₁ and X₂ are deuterium, Y₁ and Y₂ arehydrogen, and R is

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (II-b) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein X₁ and X₂ are deuterium, Y₁ and Y₂ arehydrogen, and R is

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ and R₁₀ are independently selected fromhydrogen, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (II-c) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein X₁ and X₂ are deuterium, Y₁ and Y₂ arehydrogen, and R is

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₁₀ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl. For some embodiments, R₁₀ is a partially orfully deuterated methyl or ethyl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (II-d) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (II-e) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (II-f) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (II-g) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (II-h) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (II-i) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (II-j) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is a partially or fully deuterated alkyl. Forsome embodiments, R₈ is a partially or fully deuterated methyl or ethyl.

For some embodiments, R₉ is selected from hydrogen, unsubstituted orsubstituted alkyl, unsubstituted or substituted allyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl.

For some embodiments, unsubstituted or substituted alkyl is anunsubstituted or partially or fully deuterated methyl or ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, X₁ and X₂ are deuterium.

For some embodiments, Y₁ and Y₂ are hydrogen or deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl. For someembodiments, R₂ is independently selected from hydrogen, deuterium,halogen, and an unsubstituted or partially or fully deuterated methyl orethyl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl. For some embodiments, R₈ is a partially orfully deuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₄ is hydroxyl and R₂, R₅, R₆, and R₇ are allhydrogen, R₈ and R₉ are not both -CD₃, and R₈ and R₉ are not bothunsubstituted methyl when R₂, R₄, R₅, R₆, and R₇ are all hydrogen.

For some embodiments, when R₄ is hydroxyl, R₉ is hydrogen.

For some embodiments, when R₄ is hydroxyl, R₉ is deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

For some embodiments, the compound of formula (III) is a compoundaccording to Formula (III-a), Formula (III-b), Formula (III-c), Formula(III-d), Formula (III-e), Formula (III-f), Formula (III-g), Formula(III-h), Formula (III-i), Formula (III-j), Formula (III-k), Formula(III-l), Formula (III-m), Formula (III-n), Formula (III-o), Formula(III-p), Formula (III-q), Formula (III-r), Formula (III-s), Formula(III-t), Formula (III-u), or Formula (III-v), described below.

Disclosed herein is a compound according to Formula (III-a) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₄ is hydroxyl and R₂, R₅, R₆, and R₇ are allhydrogen, R₈ and R₉ are not both -CD₃, and R₈ and R₉ are not bothunsubstituted methyl when R₂, R₄, R₅, R₆, and R₇ are all hydrogen.

For some embodiments, when R₄ is hydroxyl, R₉ is hydrogen or deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (III-b) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted methyl whenR₂, R₆, and R₇ are all hydrogen.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-c) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-d) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₂, R₆, and R₇ are all hydrogen, R₈ and R₉are not both -CD₃.

For some embodiments, R₉ is hydrogen.

For some embodiments, R₉ is deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-e) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-f) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-g) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-h) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-i) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-j) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-k) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl,

For some embodiments, R₄ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstitutedor substituted acetoxy, and phosphoryloxy.

For some embodiments, R₅ is independently selected from hydrogen,deuterium, hydroxyl, unsubstituted or substituted alkoxy, andphosphoryloxy.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₄ is hydroxyl and R₂, R₅, R₆, and R₇ are allhydrogen, R₈ and R₉ are not both -CD₃, and R₈ and R₉ are not bothunsubstituted methyl when R₂, R₄, R₅, R₆, and R₇ are all hydrogen.

For some embodiments, when R₄ is hydroxyl, R₉ is hydrogen or deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl. For some embodiments, alkoxy is methoxy or ethoxy.

Disclosed herein is a compound according to Formula (III-l) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted methyl whenR₂, R₆, and R₇ are all hydrogen.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-m) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-n) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, when R₂, R₆, and R₇ are all hydrogen, R₈ and R₉are not both -CD₃.

For some embodiments, R₉ is hydrogen.

For some embodiments, R₉ is deuterium.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-o) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-p) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-q) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-r) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen,

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-s) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-t) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-u) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

Disclosed herein is a compound according to Formula (III-v) or anoptically pure stereoisomer, pharmaceutically acceptable salt, solvate,or prodrug thereof.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, unsubstituted or substituted alkyl, unsubstituted orsubstituted allyl, unsubstituted or substituted alkenyl, unsubstitutedor substituted alkynyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.

For some embodiments, R₆ and R₇ are selected from hydrogen, deuterium,and halogen.

For some embodiments, R₈ is an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₉ is hydrogen, deuterium, or an unsubstituted orpartially or fully deuterated methyl or ethyl.

For some embodiments, R₂ is independently selected from hydrogen,deuterium, halogen, and an unsubstituted or partially or fullydeuterated methyl or ethyl.

For some embodiments, R₈ and R₉ are not both unsubstituted or partiallyor fully deuterated ethyl.

For some embodiments, substituted means partially or fully substitutedwith deuterium, e.g., substituted alkyl is a partially or fullydeuterated alkyl.

For some embodiments, the compound is selected from:

For some embodiments, the compound has the following structure:

For some embodiments, the compounds described herein have at least oneof R₂, R₄, R₅, R₆, R₇, R₉, and R₁₀ is deuterium or substituted with adeuterium.

For some embodiments, the compounds described herein have at least oneof R₂, R₄, R₅, R₆, and R₇ is deuterium or substituted with a deuterium.

For some embodiments, R₂ of the compounds described herein is deuteriumor substituted with a deuterium.

For some embodiments, R₄ of the compounds described herein is deuteriumor substituted with a deuterium.

For some embodiments, R₅ of the compounds described herein is deuteriumor substituted with a deuterium.

For some embodiments, R₆ of the compounds described herein is deuteriumor substituted with a deuterium.

For some embodiments, R₇ of the compounds described herein is deuteriumor substituted with a deuterium.

For some embodiments, R₉ of the compounds described herein is deuteriumor substituted with a deuterium.

For some embodiments, R₁₀ of the compounds described herein is deuteriumor substituted with a deuterium.

For some embodiments, R₆ and/or R₇ of the compounds described herein ishalogen.

For some embodiments, R₄ and/or R₅ of the compounds described herein isdeuterium or substituted with a deuterium.

For some embodiments, the compound is an agonist of a serotonin 5-HT₂receptor.

For some embodiments, the compound can be agonists of a serotonin5-HT_(2A) receptor.

Without being bound to any particular theory, it is believed that thenovel compounds described herein having selective deuteration, like inthe exocyclic moiety, allow for significant slowing of enzymaticdegradation with improved exposure (i.e., prevention of high drugconcentrations (spiking) observed acutely after administration) andincreased blood-to-brain ratio, resulting in enhanced oralbioavailability. Some compounds described herein confer similar benefitsby selective deuteration of the phenyl ring.

Also disclosed herein is a pharmaceutical composition comprising acompound as disclosed herein and a pharmaceutically acceptable vehicle.

“Pharmaceutically acceptable vehicles” may be vehicles approved by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized pharmacopeia for use inmammals, such as humans. The term “vehicle” refers to a diluent,adjuvant, excipient, or carrier with which a compound of the presentdisclosure is formulated for administration to a mammal. Suchpharmaceutical vehicles can be liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical vehicles can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating and coloring agents maybe used.

When administered to a mammal, the compounds and compositions of thepresent disclosure and pharmaceutically acceptable vehicles, excipients,or diluents may be sterile. In some instances, an aqueous medium isemployed as a vehicle when the subject compound is administeredintravenously, such as water, saline solutions, and aqueous dextrose andglycerol solutions.

Pharmaceutical compositions can take the form of capsules, tablets,pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions,suspensions, emulsions, suppositories, or sustained-release formulationsthereof, or any other form suitable for administration to a mammal. Insome instances, the pharmaceutical compositions are formulated foradministration in accordance with routine procedures as a pharmaceuticalcomposition adapted for oral or intravenous administration to humans.Examples of suitable pharmaceutical vehicles and methods for formulationthereof are described in Remington: The Science and Practice ofPharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19thed., 1995, Chapters 86, 87, 88, 91, and 92, incorporated herein byreference. The choice of excipient will be determined in part by theparticular compound, as well as by the particular method used toadminister the composition. Accordingly, there is a wide variety ofsuitable formulations of the subject pharmaceutical compositions.

Administration of the subject compounds may be systemic or local. Incertain embodiments administration to a mammal will result in systemicrelease of a compound of the present disclosure (for example, into thebloodstream). Methods of administration may include enteral routes, suchas oral, buccal, sublingual, and rectal; topical administration, such astransdermal and intradermal; administration by inhalation via, forexample a nebulizer or inhaler, and parenteral administration.

In some embodiments, the compositions include a compound as disclosedherein at a purity of at least 50% by weight of the total amount ofisotopologues of formula present. In some embodiments, any position inthe compound having deuterium has a minimum deuterium incorporation ofat least 45% at the deuterium. In some embodiments, the composition issubstantially free of other isotopologues of the compound.

In some embodiments, the pharmaceutical composition includes: (i) awater-insoluble neutrally charged non-ionic matrix; and (ii) a polymercarrying one or more negatively charged groups.

In some embodiments, the non-ionic matrix is selected fromcellulose-based polymers such as HPMC, alone or enhanced by mixing withcomponents such as starches; waxes; neutral gums; polymethacrylates;PVA; PVA/PVP blends; or mixtures thereof. In some embodiments, thecellulose-based polymer is hydroxypropyl methylcellulose (HPMC).

In some embodiments, the polymer carrying one or more negatively chargedgroups is polyacrylic acid, polylactic acid, polyglycolic acid,polymethacrylate carboxylates, cation-exchange resins, clays, zeolites,hyaluronic acid, anionic gums, salts thereof, or mixtures thereof.

In some embodiments, the anionic gum is a naturally occurring materialor a semi-synthetic material. In some embodiments, the naturallyoccurring material is alginic acid, pectin, xanthan gum, carrageenan,locust bean gum, gum arabic, gum karaya, guar gum, gum tragacanth, ormixtures thereof. In some embodiments, the semi-synthetic material iscarboxymethyl-chitin, cellulose gum, or mixtures thereof.

In some embodiments, provided is a modified release oral formulation. Insome embodiments, the oral formulation is for low dose maintenancetherapy that can be constructed using either deuterated ornon-deuterated tryptamines, capitalizing on the ability of tryptaminesto bind with anionic polymers.

The pharmaceutical composition may be prepared and administered in awide variety of dosage formulations. Compounds described may beadministered orally, rectally, via inhalation, or by injection (e.g.,intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally).

For preparing pharmaceutical compositions from compounds describedherein, pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substance that may also act as diluents,flavoring agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material.

In powders, the carrier may be a finely divided solid in a mixture withthe finely divided active component. In tablets, the active componentmay be mixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets can contain from about 5% to about 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

A pharmaceutical preparation can be in unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from about 0.001 mg to about 10 mg (e.g., about0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0, 2.0, 3.0. 4.0, 5.0, 6.0, 7.0,8.0, 9.0, 10.0 mg or more; or any range between about 0.001 and about10.0 mg (e.g., between about 0.0001 and about 0.1, between about 0.1 and1.0, between about 0.0005 and 0.5, or between about 0.01 and about 2.0mg), according to the particular application and the potency of theactive component. The composition can, if desired, also contain othercompatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight. Viscosity greater than that of simple aqueoussolutions may be desirable to decrease variability in dispensing theformulations, to decrease physical separation of components of asuspension or emulsion of formulation, and/or otherwise to improve theformulation. Such viscosity building agents include, for example,polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose, chondroitin sulfate and salts thereof,hyaluronic acid and salts thereof, and combinations of the foregoing.Such agents are typically employed at a level between about 0.01% andabout 2% by weight.

The pharmaceutical compositions may additionally include components toprovide sustained release and/or comfort. Such components include highmolecular weight, anionic mucomimetic polymers, gelling polysaccharides,and finely-divided drug carrier substrates. These components arediscussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841;5,212,162; and 4,861,760. The entire contents of these patents areincorporated herein by reference in their entirety for all purposes.

The pharmaceutical composition may be intended for intravenous use. Thepharmaceutically acceptable excipient can include buffers to adjust thepH to a desirable range for intravenous use. Many buffers includingsalts of inorganic acids such as phosphate, borate, and sulfate areknown.

The pharmaceutical composition may include compositions wherein theactive ingredient is contained in a therapeutically effective amount,i.e., in an amount effective to achieve its intended purpose. The actualamount effective for a particular application will depend, inter alia,on the condition being treated.

The dosage and frequency (single or multiple doses) of compoundsadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated; presence of other diseases or otherhealth-related problems; kind of concurrent treatment; and complicationsfrom any disease or treatment regimen. Other therapeutic regimens oragents can be used in conjunction with the methods and compoundsdisclosed herein.

Therapeutically effective amounts for use in humans may be determinedfrom animal models. For example, a dose for humans can be formulated toachieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring response of theconstipation or dry eye to the treatment and adjusting the dosageupwards or downwards, as described above.

Dosages may be varied depending upon the requirements of the subject andthe compound being employed. The dose administered to a subject, in thecontext of the pharmaceutical compositions presented herein, should besufficient to effect a beneficial therapeutic response in the subjectover time. The size of the dose also will be determined by theexistence, nature, and extent of any adverse side effects. Generally,treatment is initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compounds effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is entirely effective to treat the clinicalsymptoms demonstrated by the particular patient. This planning shouldinvolve the careful choice of active compound by considering factorssuch as compound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration, and the toxicity profile of the selected agent.

Also disclosed is a method of treating a subject with a disease ordisorder comprising administering to the subject a therapeuticallyeffective amount of a compound as disclosed herein.

Also disclosed is a method of treating a subject with a disease ordisorder comprising administering to the subject a therapeuticallyeffective amount of a compound as disclosed herein.

Also disclosed is a method of treating a subject with a disease ordisorder associated with a serotonin 5-HT₂ receptor comprisingadministering to the subject a therapeutically effective amount of acompound as disclosed herein. In some embodiments, the compound has thefollowing structure:

For some embodiments, the administration of the disclosed methods is byoral, sublingual, buccal, parenteral, topical, nasal, inhalation, orinjectable route.

For some embodiments, the disease or disorder is selected from the groupconsisting of central nervous system (CNS) disorders, including majordepressive disorder (MDD), major depressive disorder (MDD) with suicidalideation or suicidal behavior, suicidal ideation, suicidal behavior,non-suicidal self-injury disorder (NSSID), treatment-resistantdepression (TRD), post-traumatic stress disorder (PTSD), bipolar andrelated disorders including bipolar I disorder, bipolar II disorder,cyclothymic disorder, obsessive-compulsive disorder (OCD), generalizedanxiety disorder (GAD), social anxiety disorder, substance use disordersincluding alcohol use disorder, opioid use disorder, amphetamine usedisorder, nicotine use disorder, and cocaine use disorder, anorexianervosa, bulimia nervosa, Alzheimer's disease, cluster headache andmigraine, attention deficit hyperactivity disorder (ADHD), pain andneuropathic pain, aphantasia, childhood-onset fluency disorder, majorneurocognitive disorder, mild neurocognitive disorder, sexualdysfunction, chronic fatigue syndrome, Lyme Disease, and obesity, orcombinations thereof. In some embodiments, the disease or disorder isalcohol use disorder.

For some embodiments, the disease or disorder includes conditions of theautonomic nervous system (ANS).

For some embodiments, the disease or disorder includes pulmonarydisorders including asthma and chronic obstructive pulmonary disorder(COPD).

For some embodiments, the disease or disorder includes cardiovasculardisorders including atherosclerosis.

Also disclosed is a method of treating a subject with alcohol usedisorder associated with a serotonin 5-HT₂ receptor comprisingadministering to the subject a therapeutically effective amount of acompound having the following structure:

Formulations

Also disclosed herein is a pharmaceutical composition, e.g., apharmaceutical composition formulated for oral administration, such aspills (e.g., tablets, capsules, caplets, troaches, lozenges, caches,gelcaps, caps, pellets, boluses, pastilles, orally disintegratingtablets, sublingual tablets and buccal tablets), formulated for oraladministration, e.g., single-layer tablet composition, comprising atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, with reduced neurological adverse effectscompared to existing oral formulations. The pharmaceutical compositionis formulated to ensure the steady release of a therapeuticallyeffective concentration of tryptamine derivatives described herein froman oral pharmaceutical composition without sedative or psychotomimetictoxic spikes in plasma concentration of any of the compounds describedherein (e.g., a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof). Such spikes in plasmaconcentration have been well-documented to have serious psychotomimeticdirected side effects including, but not limited to hallucination,dizziness, and nausea; which can not only have immediate repercussions,but also adversely affect treatment compliance. In this regard, thedisclosure provides novel and inventive formulations for oraladministration comprising, e.g., optimal matrices discovered for thelong-term steady release of a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, with reducedsedative and psychotomimetic side effects.

In some embodiments, the pharmaceutical composition (e.g., a tabletcomposition formulated for oral administration such as a single-layertablet composition), comprises any of the compounds described herein(e.g., a tryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, andpsilocin, or any of the compounds described herein), or apharmaceutically acceptable salt thereof. In some embodiments, thecompound has the following structure:

In some embodiments of the disclosure, the tablet composition is amodified-release tablet adapted for sustained release, e.g., maximumsustained release.

In some embodiments of the disclosure, the tablet composition is adaptedfor tamper resistance. In some embodiments, the tablet compositioncomprises polyethylene oxide (PEO), e.g., MW about 2,000 to about 7,000KDa, in combination with HPMC. In some embodiments, the tabletcomposition may further comprise polyethylene glycol (PEG), e.g., PEG8K. In some embodiments, the tablet composition may further comprisepolymer carrying one or more negatively charged groups, e.g.,polyacrylic acid. In specific embodiments, the tablet compositioncomprising PEO is further subjected to heating/annealing, e.g.,extrusion conditions.

In some embodiments of the disclosure, the pharmaceutical compositioncomprises a combination of (i) a water-insoluble neutrally chargednon-ionic matrix; (ii) a polymer carrying one or more negatively chargedgroups; and (iii) a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof.

In some embodiments of the disclosure, the polymer carrying one or morenegatively charged groups is polyacrylic acid, polylactic acid,polyglycolic acid, polymethacrylate carboxylates, cation-exchangeresins, clays, zeolites, hyaluronic acid, anionic gums, salts thereof,or mixtures thereof. In some embodiments, the anionic gum is a naturallyoccurring material, a semi-synthetic material, or a combination thereof.In some embodiments, the naturally occurring material is alginic acid,pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, gumkaraya, guar gum, gum tragacanth, or combinations thereof. In anotherembodiment, the semi-synthetic material is carboxymethyl-chitin,cellulose gum, or combinations thereof.

Moreover, without wishing to be bound by theory, in some embodiments,the role of the polymer carrying one or more negatively charged groups,e.g., moieties of acidic nature as in those of the acidic polymersdescribed herein, surprisingly offers significant retention of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the matrix. In some embodiments, thisnegative charge may be created in situ, for example, based on release ofa proton due to pKa and under certain pH conditions or throughelectrostatic interaction/creation of negative charge. Further notingthat acidic polymers may be the salts of the corresponding weak acidsthat will be the related protonated acids in the stomach; which, andwithout wishing to be bound by theory, will neutralize the charge andmay reduce the interactions of the tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, with the matrix.In addition, the release matrix may be further complemented by otherinactive pharmaceutical ingredients to aid in preparation of theappropriate solid dose form such as fillers, disintegrants, flowimproving agents, lubricants, colorants, and taste maskers.

In some embodiments of the disclosure, the tablet composition is adaptedfor tamper resistance. In some embodiments, the tablet compositioncomprises polyethylene oxide (PEO), e.g., MW about 2,000 to about 7,000KDa. In specific embodiments, the tablet composition comprising PEO isfurther subjected to heating/annealing, e.g., extrusion.

In some embodiments of the disclosure, the non-ionic matrix is selectedfrom cellulose-based polymers such as HPMC, alone or enhanced by mixingwith components such as starches; waxes; neutral gums;polymethacrylates; PVA; PVA/PVP blends; or mixtures thereof.

In some embodiments of the disclosure, the cellulose-based polymer ishydroxypropyl methylcellulose (HPMC). In some embodiments, the tabletcomposition comprises about 20-60% hydroxypropyl methylcellulose byweight, about 10-30% starch by weight, or any combination thereof.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for thetreatment of pain. In some embodiments, the pain treated is cancer pain,e.g., refractory cancer pain. In some embodiments, the pain treated ispost-surgical pain. In some embodiments, the pain treated is orthopedicpain. In some embodiments, the pain treated is back pain. In someembodiments, the pain treated is neuropathic pain. In some embodiments,the pain treated is dental pain. In some embodiments, the pain treatedis chronic pain in opioid-tolerant patients.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for thetreatment of depression.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for thetreatment of brain injury.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for thetreatment of stroke.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use inmigraine, e.g., with aura.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use inrefractory asthma.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating alcohol dependence.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating post-traumatic stress disorder (PTSD).

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating depression (e.g., treatment resistant depression (TRD) orbipolar depression).

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating major depressive disorder (MDD).

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating anxiety (e.g., generalized anxiety disorder).

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating schizophrenia.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating bipolar disorder.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating suicidality or suicidal ideation.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating autism.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating diabetic neuropathy.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating neuropathic pain.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating acute pain (e.g., acute trauma pain).

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating chronic pain.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating levodopa-induced dyskinesia.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating or modulating a speudobulbar effect or Bulbar function.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating Alzheimer's disease or conditions associated with Alzheimer'sdisease (e.g., Alzheimer's dementia or Alzheimer's agitation).

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating tinnitus.

In some embodiments, the tablet composition comprises a therapeuticallyeffective amount of any of the compounds described herein for use intreating a disease or disorder associated with a serotonin 5-HT₂receptor.

For some embodiments, the disease or disorder is selected from the groupconsisting of central nervous system (CNS) disorders, including majordepressive disorder (MDD), major depressive disorder (MDD) with suicidalideation or suicidal behavior, suicidal ideation, suicidal behavior,non-suicidal self-injury disorder (NSSID), treatment-resistantdepression (TRD), post-traumatic stress disorder (PTSD), bipolar andrelated disorders including bipolar I disorder, bipolar II disorder,cyclothymic disorder, obsessive-compulsive disorder (OCD), generalizedanxiety disorder (GAD), social anxiety disorder, substance use disordersincluding alcohol use disorder, opioid use disorder, amphetamine usedisorder, nicotine use disorder, and cocaine use disorder, anorexianervosa, bulimia nervosa, Alzheimer's disease, cluster headache andmigraine, attention deficit hyperactivity disorder (ADHD), pain andneuropathic pain, aphantasia, childhood-onset fluency disorder, majorneurocognitive disorder, mild neurocognitive disorder, sexualdysfunction, chronic fatigue syndrome, Lyme Disease, and obesity, orcombinations thereof. In some embodiments, the disease or disorder isalcohol use disorder.

For some embodiments, the disease or disorder includes conditions of theautonomic nervous system (ANS).

For some embodiments, the disease or disorder includes pulmonarydisorders including asthma and chronic obstructive pulmonary disorder(COPD).

For some embodiments, the disease or disorder includes cardiovasculardisorders including atherosclerosis.

Depression, anxiety, or stress can be common among patients who havechronic and/or life-threatening illnesses such as Alzheimer's disease,autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoidarthritis, and psoriasis), cancer, coronary heart disease, diabetes,epilepsy, HIV/AIDS, hypothyroidism, multiple sclerosis, Parkinson'sdisease, and stroke. Symptoms of depression, anxiety, or stress canoccur after diagnosis with the disease or illness. Patients that havedepression, anxiety, or stress concurrent with another medical diseaseor illness can have more severe symptoms of both illnesses and symptomsof depression, anxiety, or stress can continue even as a patient'sphysical health improves. Compounds and formulations described hereincan be used to treat depression associated with a chronic orlife-threatening disease or illness.

In some embodiments, the tablet composition comprises an amount of anyof the compounds described herein released from the matrix with a rate0.05-2 mg/kg/h over a period of 12-24 hours, e.g., 24 hours.

In some embodiments of the disclosure, the composition achieves acombined concentration of a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, in plasma in therange of about 10-500 ng/ml (e.g., about 10, 20, 30, 40, 50, 100, 150,200, 250, 300, 350, 400, 450, 500 or more ng/ml (or any range betweenabout 10 and about 500 ng/ml, e.g., about 100 to about 300 ng/ml, about250 to about 450 ng/ml, or about 50 to about 400 ng/ml), and maintainsthis concentration for duration of the release period. In someembodiments, the composition achieves a combined concentration of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in plasma in the range of about 10-300 ng/ml,and maintains this concentration for duration of the release period. Insome embodiments, the composition achieves a combined concentration of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in plasma in the range of about 10-100 ng/ml,or about 50-100 ng/ml, and maintains this concentration for duration ofthe release period. In some embodiments, the composition achieves acombined concentration of a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, in plasma in therange of about 10-20 ng/ml, and maintains this concentration forduration of the release period.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure is 4hours or less, 3 hours or less, 2 hours or less, or 1 hour or less.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than 4 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than about 8 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than about 12 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than about 16 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than about 20 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than or equal to about 24 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than or equal to about 28 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than or equal to about 32 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure isgreater than or equal to about 36 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure is lessthan about 48 hours.

In some embodiments of the disclosure, the release period of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, in the formulations of the disclosure is lessthan about 36 hours.

In some embodiments of the disclosure, the tablet compositions of thedisclosure are utilized as a 2-times a day (BID), 3-times a day (TID) or4-times a day (QID) application.

In some embodiments of the disclosure, the tablet compositions of thedisclosure are utilized as a once a day (QD) application.

In some embodiments of the disclosure, the tablet compositions of thedisclosure are utilized as a nightly (QHS) application.

In some embodiments of the disclosure, the tablet compositions of thedisclosure are utilized as an as needed (PRN) application.

In some embodiments of the disclosure, the oral pharmaceuticalcompositions are enhanced. In some embodiments, due to the efficiency ofadministration, the formulation is able to utilize less of a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, fortreatment to achieve the same effect as comparative oral tablets notdescribed by the disclosure.

In some embodiments of the disclosure, the oral administration event,which provides the appropriate single unit dose, may comprise one singlepill or multiple pills.

In addition, to protect the tablet from the acidic environment in thestomach and maintain a long-term release, various types of entericcoating may be used in some embodiments.

In some embodiments of the disclosure, a single-layer tablet or capletis coated with protective layers of inactive pharmaceutical ingredientsto form a modified-release formulation, e.g., to ensure steady releaseof the drug from the matrix and avoid concentration bursts at the earlyrelease time points.

Some embodiments of the disclosure provides formulation of a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof as a modified-release formulation, that ensures the steadyrelease of a therapeutically effective concentration of a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof, from such oral modified-release formulation, without sedativeor psychotomimetic toxic spikes in plasma concentration of any of thecompounds described herein (e.g., a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof). This formulationcomprises a tryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin,and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, formulated in an osmoticcontrolled release pharmaceutical composition, such as a tablet, capletor granules. In these formulations a single core layer containing atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof (e.g., as defined by other tablet formulationsdescribed herein), is surrounded by semi-permeable membrane with orwithout drug delivery orifice. Without wishing to be bound by theory,because these systems use water osmotic pressure for the controlleddelivery of the active material, delivery rates are expected to beindependent of gastrointestinal conditions. In combination with thenovel and inventive aspects of the disclosure, osmoticasymmetric-membrane technology or AMT (e.g., technology directed to asingle-layer tablet, caplet or granules coated with an insoluble,asymmetric microporous membrane produced by controlled phase separation)may be used to produce formulations useful in the methods of treatmentand kits described herein.

In some embodiments of the disclosure, a tryptamine derivative, such asDMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt thereof, may beformulated as a pharmaceutically acceptable salt thereof, e.g.,hydrochloride, aspartate, succinate, etc., such that the counterion doesnot significantly affect formulation as described herein for atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, or the ability of a tryptamine derivative, suchas DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt thereof, toachieve the desired therapeutic effects described herein, i.e., withsimilar steady release of a therapeutically effective concentration(e.g., based on indication) from an oral pharmaceutical composition,such as a tablet, a caplet, a capsule, a gelcap, a cap or granules,without sedative or psychotomimetic toxic spikes in the concentration ofa tryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, andpsilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof. Exemplary salts, within thisscope, may include but are not limited to: salts with an inorganic acidsuch as hydrochloric acid, hydrobromic acid, hydriodic acid, nitricacid, perchloric acid, sulfuric acid or phosphoric acid; and salts withan organic acid, such as methanesulfonic acid, trifluoromethanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid,tartaric acid; and other mineral and carboxylic acids well known tothose skilled in the art. Additional examples may include salts withinorganic cations such as sodium, potassium, calcium, magnesium,lithium, aluminum, zinc, etc.; and salts formed with pharmaceuticallyacceptable amines such as ammonia, alkylamines, hydroxyalkylamines,lysine, arginine, N-methylglucamine, procaine and the like. In specificembodiments, the pharmaceutically acceptable salt is a hydrochloridesalt.

Some embodiments of the disclosure provides a kit for the treatment of asubject with a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, comprising pharmaceuticalcomposition, such as an orally administered pharmaceutical compositionlike a pill, of any one of the formulations described herein comprisinga tryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, andpsilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment, prevention or management of a disease, disorder orcondition, such as pain, e.g., as described herein.

In some embodiments of the disclosure, the pain treated is cancer pain,e.g., refractory cancer pain.

In some embodiments of the disclosure, the pain treated is post-surgicalpain.

In some embodiments of the disclosure, the pain treated is orthopedicpain.

In some embodiments of the disclosure, the pain treated is back pain.

In some embodiments of the disclosure, the pain treated is neuropathicpain.

In some embodiments of the disclosure, the pain treated is dental pain.

In some embodiments of the disclosure, the pain treated is chronic painin opioid-tolerant patients.

In some embodiments, the disease or disorder is a disease or disorderassociated with a serotonin 5-HT₂ receptor.

For some embodiments, the disease or disorder is selected from the groupconsisting of central nervous system (CNS) disorders, including majordepressive disorder (MDD), major depressive disorder (MDD) with suicidalideation or suicidal behavior, suicidal ideation, suicidal behavior,non-suicidal self-injury disorder (NSSID), treatment-resistantdepression (TRD), post-traumatic stress disorder (PTSD), bipolar andrelated disorders including bipolar I disorder, bipolar II disorder,cyclothymic disorder, obsessive-compulsive disorder (OCD), generalizedanxiety disorder (GAD), social anxiety disorder, substance use disordersincluding alcohol use disorder, opioid use disorder, amphetamine usedisorder, nicotine use disorder, and cocaine use disorder, anorexianervosa, bulimia nervosa, Alzheimer's disease, cluster headache andmigraine, attention deficit hyperactivity disorder (ADHD), pain andneuropathic pain, aphantasia, childhood-onset fluency disorder, majorneurocognitive disorder, mild neurocognitive disorder, sexualdysfunction, chronic fatigue syndrome, Lyme Disease, and obesity, orcombinations thereof. In some embodiments, the disease or disorder isalcohol use disorder.

For some embodiments, the disease or disorder includes conditions of theautonomic nervous system (ANS).

For some embodiments, the disease or disorder includes pulmonarydisorders including asthma and chronic obstructive pulmonary disorder(COPD).

For some embodiments, the disease or disorder includes cardiovasculardisorders including atherosclerosis.

Some embodiments of the disclosure provides a kit for the treatment of asubject with a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, comprising a pharmaceuticalcomposition, such as an orally administered tablet pharmaceuticalcomposition like a pill, of any one of the formulations of thedisclosure comprising a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of brain injury.

Some embodiments of the disclosure provides a kit for the treatment of asubject with a tryptamine derivative, such as DMT, formula, psilocybin,and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, comprising a pharmaceuticalcomposition, such as an orally administered tablet pharmaceuticalcomposition like a pill, of any one of the formulations of thedisclosure comprising a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of depression.

Some embodiments of the disclosure provides a kit for the treatment of asubject with a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, comprising a pharmaceuticalcomposition, such as an orally administered tablet pharmaceuticalcomposition like a pill, of the formulations of the disclosurecomprising a tryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin,and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of migraine, e.g., with aura.

Some embodiments of the disclosure provides a kit for the treatment of asubject with a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, comprising a pharmaceuticalcomposition, such as an orally administered tablet pharmaceuticalcomposition like a pill, of the disclosure comprising a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof, and instructions for use in the treatment of refractory asthma.

Some embodiments of the disclosure provides a kit for the treatment of asubject with a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, comprising a pharmaceuticalcomposition, such as an orally administered tablet pharmaceuticalcomposition like a pill, of any one of the formulations of thedisclosure comprising a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of stroke.

Some embodiments of the disclosure provides a kit for the treatment of asubject with a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, comprising a pharmaceuticalcomposition, such as an orally administered tablet pharmaceuticalcomposition like a pill, of any one of the formulations of thedisclosure comprising a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of alcohol dependence.

In some embodiments, the instructions for use form an integratedcomponent of the packaging for the tablet composition.

In embodiments, the disclosure features an oral, modified-releasepharmaceutical composition for oral administration to a subject fortreating the subject diagnosed with, suffering from or susceptible to adisease, disorder or condition, such as those for which tryptaminetreatment may be indicated, considered or recommended, wherein thesubject is in need of treatment with said oral, modified-releasepharmaceutical composition, said oral, modified-release pharmaceuticalcomposition comprising:

(a) a drug including a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof in an effective amount fortreating, preventing and/or managing the disease, disorder, or conditionin the subject; and

(b) a pharmaceutically acceptable excipient;

whereby, upon oral administration of the modified-release pharmaceuticalcomposition to the subject, a steady release of said drug from themodified-release pharmaceutical composition is maintained so that noneurologically toxic spike in the subject's plasma occurs during therelease period of said drug from said pharmaceutical composition.

General Tablet Formulations

The formulations of the disclosure comprise orally administeredpharmaceutical compositions, such as tablet, capsule, caplets, gelcapand cap compositions, which may include uncoated tablets or coatedtablets, caplets and caps (including film-coated, sugar-coated tablets,and gastro-resistant/enteric-coated tablets). The oral pharmaceuticalcompositions for oral use may include the active ingredients, e.g., atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, mixed with pharmaceuticallyacceptable inactive excipients such as diluents, disintegrating agents,binding agents, lubricating agents, powder flow improving agent, wettingagents, sweetening agents, flavoring agents, coloring agents andpreservatives. Moreover, oral pharmaceutical compositions of thedisclosure are solid dosage forms intended for oral administration,e.g., obtained by dry granulation with single or multiple compressionsof powders or granules. In some embodiments, the oral pharmaceuticalcompositions may be obtained by using wet granulation techniques. Insome embodiments, the oral pharmaceutical compositions may be obtainedby molding, heating/annealing, or extrusion techniques.

In some embodiments, the oral tablets are right circular solidcylinders, the end surfaces of which are flat or convex, and the edgesof which may be beveled. In some embodiments, the surfaces are convex.In addition, they may have lines or break-marks (scoring), symbols orother markings.

In some embodiments, the break-mark(s) is/are intended to permitaccurate subdivision of the tablet in order to provide doses of lessthan one tablet. In some embodiments of the disclosure, the tabletcompositions comprise one or more excipients such as diluents, binders,disintegrating agents, glidants, lubricants, substances capable ofmodifying the behavior of the dosage forms and the active ingredient(s)in the gastrointestinal tract, coloring matter authorized by theappropriate national or regional authority and flavoring substances.When such excipients are used it is necessary to ensure that they do notadversely affect the stability, dissolution rate, bioavailability,safety or efficacy of the active ingredient(s); there must be noincompatibility between any of the components of the dosage form.

Coated tablets are tablets covered with one or more layers of mixturesof substances such as natural or synthetic resins, polymers, gums,fillers, sugars, plasticizers, polyols, waxes, coloring mattersauthorized by the appropriate national or regional authority, andflavoring substances. Such coating materials do not contain any activeingredient, e.g., a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof. The tablets may be coated fora variety of reasons such as protection of the active ingredients fromburst release from the matrix, air, moisture or light, masking ofunpleasant tastes and odors or improvement of appearance. The substanceused for coating may be applied as a solution or suspension.

In some embodiments, the manufacturing processes for the oralpharmaceutical compositions, e.g., tablets, meet the requirements ofgood manufacturing practices (GMP). In some embodiments, one or moremeasures are taken in the manufacture of oral pharmaceuticalcompositions selected from the following: ensure that mixing withexcipients is carried out in a manner that ensures homogeneity; ensurethat the oral pharmaceutical compositions possess a suitable mechanicalstrength to avoid crumbling or breaking on subsequent processing, e.g.,coating, storage and distribution; minimize the degradation of theactive ingredient; minimize the risk of microbial contamination;minimize the risk of cross-contamination. In addition, in themanufacture of scored tablets (tablets bearing a break-mark or marks)for which subdivision is intended in order to provide doses of less thanone tablet measures are taken to: ensure the effectiveness ofbreak-marks with respect to the uniformity of mass or content, asappropriate, of the subdivided parts so that the patient receives theintended close.

In general a suitable dose will be in the range of about 0.01 to about10 mg per kilogram body weight of the recipient per day, e.g., in therange of about 0.1 to about 5 mg per kilogram body weight per day.Additional details on techniques for formulation and administration arewell described in the scientific and patent literature, see, e.g., thelatest edition of Remington's Pharmaceutical Sciences, Maack PublishingCo, Easton Pa. (“Remington's”). After a pharmaceutical composition hasbeen formulated in an acceptable carrier, it can be placed in anappropriate container and labeled for treatment of an indicatedcondition). For administration of the formulations comprising any of thecompounds described herein (e.g., a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein), or a pharmaceutically acceptable salt thereof, such labelingwould include, e.g., instructions concerning the amount, frequency,method of administration, treatment regimen and indications.

Compliance with Monographs

In some embodiments, the formulations of the disclosure conform tocertain industry accepted monographs to afford compliance with theFederal Food Drug and Cosmetic Act. In particular, the formulations ofthe disclosure conform and are considered acceptable under visualinspection, uniformity of mass analysis, uniformity of content analysis,and/or dissolution/disintegration analysis all of which are establishedby a relevant monograph.

In some embodiments, throughout manufacturing certain procedures arevalidated and monitored by carrying out appropriate in-process controls.These are designed to guarantee the effectiveness of each stage ofproduction. In-process controls during tablet production may include themoisture content of the final lubricated blend, the size of granules,the flow of the final mixture and, where relevant, the uniformity ofmass of tablet cores before coating. In-process controls during tabletproduction may also include the dimensions (thickness, diameter),uniformity of mass, hardness and/or crushing force, friability,disintegration or dissolution rate (for example, for modified-releasetablets) of the finished dosage form. Suitable test methods that may beused to demonstrate certain of these attributes arc known in the art.

In some embodiments, packaging maybe or is required to be adequate toprotect the pharmaceutical compositions, including tablets, from light,moisture and damage during transportation.

In additional embodiments, the commercially available formulation (e.g.,kit) complies with the labeling requirements established under GoodManufacturing Practices (GMP). Such label includes:

(1) the name of the pharmaceutical product;

(2) the name(s) of the active ingredient(s); InternationalNonproprietary Names (INN) should be used wherever possible;

(3) the amount of the active ingredient(s) in each tablet and the numberof tablets in the container;

(4) the batch (lot) number assigned by the manufacturer;

(5) the expiry date and, when required, the date of manufacture;

(6) any special storage conditions or handling precautions that may benecessary;

(7) directions for use, warnings, and precautions that may be necessary;

(8) the name and address of the manufacturer or the person responsiblefor placing the product on the market;

(9) for scored tablets where the directions for use include subdivisionto provide doses of less than one tablet, the label should also include:the storage conditions for and the period of use of those subdividedpart(s) not immediately taken or administered.

In some embodiments, the pharmaceutical compositions, e.g., tablets, areable to withstand handling, including packaging and transportation,without losing their integrity.

The formulations of the disclosure may be used in the methods of thedisclosure, e.g., methods of treatment of the disclosure. As such, thedisclosure relates to the method of use of formulations or compositions(e.g., pharmaceutical compositions) of the disclosure, which contain atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, e.g., for the treatment of pain. As such, insome embodiments, the disclosure provides for the management ofdifferent kinds of pain, including but not limited to refractory cancerpain, neurologic pain, postoperative pain, complex regional painsyndrome (CRPS), migraine, e.g., with aura, and other conditionsincluding depression, alcohol dependence, refractory asthma, epilepsy,acute brain injury and stroke, Alzheimer's disease and other disorderscomprising an oral administration of the formulations of the disclosure,described herein. In some embodiments, the use of formulations of thedisclosure may be used as a standalone therapy. In some embodiments, theuse of formulations of the disclosure may be used as anadjuvant/combination therapy.

In some embodiments, the disclosure provides for the management ofdifferent kinds of pain, including but not limited to cancer pain, e.g.,refractory cancer pain; neuropathic pain; opioid-induced hyperalgesiaand opioid-related tolerance; neurologic pain;postoperative/post-surgical pain; complex regional pain syndrome (CRPS);shock; limb amputation; severe chemical or thermal burn injury; sprains,ligament tears, fractures, wounds and other tissue injuries; dentalsurgery, procedures and maladies; labor and delivery; during physicaltherapy; radiation poisoning; acquired immunodeficiency syndrome (AIDS);epidural (or peridural) fibrosis; orthopedic pain; back pain; failedback surgery and failed laminectomy; sciatica; painful sickle cellcrisis; arthritis; autoimmune disease; intractable bladder pain; painassociated with certain viruses, e.g., shingles pain or herpes pain;acute nausea, e.g., pain that may be causing the nausea or the abdominalpain that frequently accompanies sever nausea; migraine, e.g., withaura; and other conditions including depression (e.g., acute depressionor chronic depression), depression along with pain, alcohol dependence,acute agitation, refractory asthma, acute asthma (e.g., unrelated painconditions can induce asthma), epilepsy, acute brain injury and stroke,Alzheimer's disease and other disorders. In addition, the disclosureincludes the treatment/management of any combination of these types ofpain or conditions.

In some embodiments, the pain treated/managed is acute breakthrough painor pain related to wind-up that can occur in a chronic pain condition.

In some embodiments of the disclosure, the pain treated/managed iscancer pain, e.g., refractory cancer pain.

In some embodiments of the disclosure, the pain treated/managed ispost-surgical pain.

In some embodiments of the disclosure, the pain treated/managed isorthopedic pain.

In some embodiments of the disclosure, the pain treated/managed is backpain.

In some embodiments of the disclosure, the pain treated/managed isneuropathic pain.

In some embodiments of the disclosure, the pain treated/managed isdental pain.

In some embodiments of the disclosure, the condition treated/managed isdepression.

In some embodiments of the disclosure, the pain treated/managed ischronic pain in opioid-tolerant patients.

In embodiments, the disclosure relates to a method of treating a diseaseor condition by modulating NMDA activity, where the method comprisesadministering an effective amount of any of the compounds describedherein (e.g., a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein) to asubject in need thereof. In embodiments, the disease or condition isselected from: levodopa-induced dyskinesia; dementia (e.g., Alzheimer'sdementia), tinnitus, treatment resistant depression (TRD), majordepressive disorder, neuropathic pain, agitation resulting from orassociated with Alzheimer's disease, pseudobulbar effect, autism, Bulbarfunction, generalized anxiety disorder, Alzheimer's disease,schizophrenia, diabetic neuropathy, acute pain, depression, bipolardepression, suicidality, neuropathic pain, or post-traumatic stressdisorder (PTSD). In embodiments, the disease or condition is apsychiatric or mental disorder (e.g., schizophrenia, mood disorder,substance induced psychosis, major depressive disorder (MDD), bipolardisorder, bipolar depression (BDep), post-traumatic stress disorder(PTSD), suicidal ideation, anxiety, obsessive compulsive disorder (OCD),and treatment-resistant depression (TRD)). In other embodiments, thedisease or condition is a neurological disorder (e.g., Huntington'sdisease (HD), Alzheimer's disease (AD), or systemic lupus erythematosus(SLE)).

For example, in some embodiments, the disclosure provides a method oftreating a subject with a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, comprising the step ofadministering to a subject an orally administered tablet composition,e.g., matrix composition, of the disclosure comprising a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof, such that the subject is treated.

The administering physician can provide a method of treatment that isprophylactic or therapeutic by adjusting the amount and timing of atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, administration on the basis of observations ofone or more symptoms of the disorder or condition being treated.

In some embodiments, the disclosure provides a method of continuous oraladministration of a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, into a tablet, e.g.,single-layer tablet, that provides a steady release of a therapeuticallyeffective concentration of a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, from an oraltablet over a complete release period without neurologically toxicspikes, e.g., no sedative or psychotomimetic toxic spikes in plasmaconcentration of a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, to produce a tabletcomposition, e.g., single-layer tablet composition; and orallyadministering the tablet composition to a subject, such that acontinuous therapeutically effective concentration of a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof, is provided to the subject.

In some embodiments of the disclosure, the subject is a mammal.

In some embodiments of the disclosure, the mammal is a human.

In some embodiments, the disclosure provides a method of formulating atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, to ensure the steady release of atherapeutically effective concentration of a tryptamine derivative, suchas DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt thereof, from anoral tablet without neurologically toxic spikes, e.g., sedative orpsychotomimetic toxic spikes, in plasma concentration of a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof. In some embodiments, the method comprises the step of combining(i) a water-insoluble neutrally charged non-ionic matrix; (ii) a polymercarrying one or more negatively charged groups; and (iii) a tryptaminederivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof, to produce an orally administered tablet composition, e.g.,single-layer. In some embodiments, the method comprises the step ofcombining (i) polyethylene oxide (PEO), e.g., MW about 2,000 to about7,000 KDa, with HPMC, and (ii) a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, to produce anorally administered tablet composition, e.g., single-layer. In someembodiments, the method comprises the step of combining polyethyleneoxide (PEO) with HPMC, and a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, the tabletcomposition may further comprise polyethylene glycol (PEG), e.g., PEG8K, a polymer carrying one or more negatively charged groups, e.g.,polyacrylic acid and/or may be further subjected to heating/annealing,e.g., extrusion conditions. In some embodiments, the formulations of thedisclosure may be administered in combination with other activetherapeutic agents, e.g., opioids to reduce pain. In some embodiments,the formulations of the disclosure serve to reduce the amount of opioidsnecessary to treat a patient.

In some embodiments, the formulations of the disclosure are notadministered in combination with other active therapeutic agents.

In some embodiments, the formulations of the disclosure may beadministered in combination with another formulation of tryptamine orderivatives thereof, e.g., a fast release formulation tryptamine orderivatives thereof.

In some embodiments, the disclosure provides a method of formulating atryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin, and psilocin,or any of the compounds described herein, or a pharmaceuticallyacceptable salt thereof, to ensure the steady release of atherapeutically effective concentration of the a tryptamine derivative,such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of thecompounds described herein, or a pharmaceutically acceptable saltthereof, from an oral tablet without sedative or psychotomimetic toxicspikes in plasma concentration of the a tryptamine derivative, such asDMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compoundsdescribed herein, or a pharmaceutically acceptable salt thereof. Themethod comprises formulation of a tryptamine derivative, such as DMT,5-MeO-DMT, psilocybin, and psilocin, or any of the compounds describedherein, or a pharmaceutically acceptable salt thereof, in an osmoticcontrolled release tablet. In these formulations the single core layercontaining a tryptamine derivative, such as DMT, 5-MeO-DMT, psilocybin,and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof, is surrounded bysemi-permeable membrane with or without drug delivery orifice. In someembodiments, combination with the novel and inventive pharmaceuticalcompositions (e.g., a tryptamine derivative, such as DMT, 5-MeO-DMT,psilocybin, and psilocin, or any of the compounds described herein, or apharmaceutically acceptable salt thereof), of the disclosure and osmoticasymmetric-membrane technology or AMT (e.g., technology directed to asingle-layer tablet coated with an insoluble, asymmetric microporousmembrane produced by controlled phase separation) may be used to produceformulations useful in the methods and kits described herein.

EXAMPLES Example 1. Synthesis of PI-α,α-d₂

Synthesis of PI-α,α-d₂ started with 4-oxybenzylindole that isiminoformylated by formaldehyde/dimethylamine and then converted to the3-acetic acid derivative using potassium cyanide in acidic conditions.Subsequent treatment with thionyl chloride and dimethylamine produces arelated amide that is reduced by LiAlD₄, which inserts adeuteromethylene group in the α-position. In the final step, the —OBzprotective group is removed by hydrogen gas over a palladium catalyst toproduce a final compound. The structure of the product has beenconfirmed by ¹H NMR and LC-MS.

Example 2. Synthesis of DMT-d₁₀

Synthesis of DMT-d₁₀ started with indole that is first acylated byoxalyl chloride and then converted to the related amide by treatmentwith dimethyl amine-d₆. Subsequent reduction with LiAlD₄ leads to thefinal product. The structure of the material has been confirmed by ¹HNMR and LC-MS.

Example 3. Synthesis of 5-CD₃O-DMP-α,α, 5,5,5-d₅

Synthesis of 5-CD₃O-DMP-α,α,5,5,5-d₅ has been conducted analogously toDMT-α,α-d₂ described in the Example 2 starting from 5-deuteromethoxyindole prepared by the methylation of 5-hydroxyindole usingdeuteromethyl iodide. The structure of the product has been confirmed by¹H NMR and LC-MS.

Example 4. Synthesis of Aer-α,α,-d₂

Synthesis of Aer-α,α-d₂ has been conducted using an —OBz bis-deuteratedtryptamine intermediate obtained as described in the Example 1. Thatmaterial has been alkylated with methylamine and then reduced byhydrogen on palladium to obtain a final product as an iodide salt(Scheme 2). The structure of the product has been confirmed by ¹H NMRand LC-MS.

Example 5. 5-HT Receptor Pharmacodynamics

Binding affinity (K_(i)) and functional potency (EC₅₀) values of PI andPI-α-d₂ are summarized in Table 1. Deuteration was found to have littleeffect on the affinity and function at key receptor targets.

Receptor Affinity Assays: 5-HT_(1A), 5-HT_(2(A,B,C)) receptor affinitieswere determined by radioligand competition binding. Membranes fromCHO-K1 or HEK293 cells expressing serotonergic receptors were collectedand incubated in assay buffer with K_(d) concentrations of radioligandsand tests compounds that compete for receptor binding sites. Afterequilibration, the reaction was terminated by collectingligand-receptor-membrane complexes (Microbeta, PerkinElmer), andradioactivity was measured by a scintillation counter (Microbeta2,PerkinElmer). Data were fit to non-linear curves, and K_(i) values werecalculated per the Cheng-Prusoff equation.

Receptor Function Assays: 5-HT_(1A) receptor-mediated Gi stimulation(reduction in cyclic adenosine monophosphate (cAMP) levels) and5-HT_(2(A,B,C)) receptor-mediated Gq stimulation (phosphoinositidehydrolysis leading to the production of inositol phosphate 1(IP1))—canonical signaling pathways—were measured as previouslydescribed (Canal et al., 2013), for example, with a homogeneoustime-resolved fluorescence (HTRF) capable microplate reader (e.g.,Mithras LB 940, Berthold) using commercially-available kits employingFluorescence Resonance Energy Transfer (FRET) technology (e.g., LANCEUltra cAMP TR-FRET (PerkinElmer) and IP-One HTRF (Cisbio) kits).Briefly, CHO-K1 or HEK293 cells expressing serotonergic receptors wereincubated with test compounds in stimulation buffer. Afterequilibration, the reaction was terminated with the donor and acceptorfluorescent conjugates in lysis buffer, and FRET was measured. Data werefit to non-linear curves to calculate potencies (e.g., EC₅₀) andefficacies (e.g., E_(MAX)), relative to positive controls (e.g.,serotonin).

TABLE 1 PI and PI-α,α-d₂ Affinities and Functions at Target SerotoninReceptors 5-HT_(1A) 5-HT_(2A) 5-HT_(2B) 5-HT_(2C) PI 567ª N.R. 107^(b)45 5ª >20,000 140^(b) N.R. PI-α,α-d₂ 510ª 200 100^(b) 40 6ª >20,000130^(b) 115 Pharmacodynamics of psilocin and deuteropsilocin at targetserotonergic receptors suggest no significant changes in ligand-receptorinteractions. Under each receptor, sub-columns report, in nM, K_(i)(agonist^(a)- or antagonist^(b)-labeled) and EC₅₀ (canonical signalingpathways) values, respectively, based on assessment at human receptors.PI data are PDSP certified or from Blough et al., 2014, Rickli et al.,2016, or Almaula et al., 1996. N.R. = not reported.

Example 6. In Vitro Liver Metabolism and Kinetic Deuterium IsotopeEffects

5-MeO-DMT and 5-MeO-DMT-α,α-d₂ (10 μl of 2 μM solution) were incubatedin 200 μl of medium that consisted of 100 mg rat liver microsomes, NADPHregenerating system (1 mM NADP, 1 unit/ml of isocitrate dehydrogenase, 5mM isocitric acid, 5 mM magnesium chloride), and 25 mM of phosphatebuffer (pH 7.4). The reaction was terminated at different time points (0to 60 min) by the addition of 300 μl of acetonitrile. For the analysesof products, the precipitated salts and proteins were spun out on acentrifuge, the residual solution diluted with 300 μl of water andinjected into the LC/MS (Agilent 1200 system interfaced with an ABSSciex 4000 QTRAP LC/MS/MS Mass Spectrometer). The metabolic stabilitywas estimated by evaluating the rate of disappearance of the main parentpeak. The observed collective kinetic deuterium isotope effect (thereaction rate decrease for deuterated vs. non-deuterated molecule) wassubstantial at 150-200%. Similar effects were observed in this assay forDMT vs. DMT-α,α-d₂ and DMT-α,α,β,β-d₄. Further enhancement of metabolicstability has been detected for DMT-d₁₀ that also showed a superiorityin the MAO-A enzymatic assay highlighting additional deuteration effectsof the —N(CD₃)₂ substituent.

TABLE 2 Results of the Determination of Metabolic Stability of Four TestArticles in the Presence of RLM CL_(int) % Remaining of InitialHalf-life (mL/min/mg Test Article 0 min 5 min 10 min 20 min 30 min 60min 120 min (min) protein)^(a) DMT 100 65.2 52.2 41.0 33.2 17.4  4.0718.2 0.0762 DMT-d₂ 100 67.5 56.6 48.8 43.3 32.0 21.5  37.0 0.0374 DMT-d₄100 70.7 59.6 51.8 46.3 34.2 23.7  42.1 0.0329 DMT-d₁₀ 100 72.5 62.255.2 50.9 39.6 29.4  55.6 0.0249 ^(a)Intrinsic clearance (CL_(int)) wascalculated based on CL_(int) = k/P, where k is the elimination rateconstant and P is the protein concentration in the incubation.

TABLE 3 Results of the Determination of Metabolic Stability of Four TestArticles in the Presence of hrMAO-A CL_(int) % Remaining of InitialHalf-life (mL/min/mg Test Article 0 min 5 min 10 min 20 min 30 min 60min 120 min (min) protein)^(a) DMT 100 96.3 90.7 64.8 49.4 18.1 3.95  27.2 0.638 DMT-d₂ 100 106 111 101 97.5 76.0 59.1 >120   0.126 (137)DMT-d₄ 100 106 111 102 98.2 77.4 61.4 >120   0.119 (145) DMT-d₁₀ 100 107112 103 101 82.2 68.6 >120   0.0953 (180)

TABLE 4 Results of the Determination of Metabolic Stability of d₈ andd₁₀ Analogs of DMT in the Presence of RLM CL_(int) % Remaining ofInitial Half-life (mL/min/mg Test Article 0 min 5 min 10 min 20 min 30min 60 min 120 min (min) protein)^(a) DMT-d₈ 100 69.8  55.9  44.0  39.2 29.7  22.7 30.5 0.0454 DMT-d₁₀ 100 69.3  56.0  44.9  39.3  30.5  23.632.2 0.0430 Percent Ratio of 100 99.3 100.2 101.9 100.2 102.6 103.8 NANA [d₁₀]/[d₈]

TABLE 5 Results of the Determination of Metabolic Stability of d₈ andd₁₀ Analogs of DMT in the Presence of hrMAO-A CL_(int) % Remaining ofInitial Half-life (mL/min/mg Test Article 0 min 5 min 10 min 20 min 30min 60 min 120 min (min) protein)^(a) DMT-d₈ 100.0 99.1 94.9 95.1 91.280.3 63.9 >120   0.177 (196) DMT-d₁₀ 100.0 99.0 94.9 95.4 91.4 81.565.8 >120   0.165 (210) Percent Ratio of 100.0 99.9 100.0 100.4 100.2101.6 102.9 NA NA [d₁₀]/[d₈]

Example 7. PK Studies in Rats and Mice

The key PK parameters (presented as a % change vs. non-deuteratedmaterials) are presented in Table 3 to include half-life (T_(1/2)), areaunder the curve (AUC), bioavailability (F) and blood-to-plasma ration(BPR). Pharmacokinetics of the deuterated tryptamines was studied inrats. In a typical experiment, run as a cassette dosing, two groups of 5Wistar female rats (200-250 g) with surgically inserted jugular veincatheter (Charles River, Andover, Mass.) were fasted for 12 h and thenadministered 5 mg/kg of the deuterated and 5 mg/kg of the relatednon-deuterated analog, by oral gavage or via a catheter for each group.At time points 0, 15, 30, 60 min, and 2, 4, 8, and 24 h, the resultingplasma was analyzed for the parent molecule using LC/MS spectroscopy.Two separate groups of 5 animals were used for determiningblood-to-plasma ratio (BPR). Each group was sacrificed at time points 15and 30 min, respectively, and the concentration of the parent drug wasdetermined in the brain and plasma by LC/MS spectroscopy.

TABLE 6 Deuterium Kinetic Isotope Effects (% change) for the Key PKParameters. BPR, BPR, Compound T_(1/2) AUC F 15 min 30 min PI-α-d₂ 50 7545 100 150 5-MeO-DMT-α,α-d₂ 30 60 200 120 180

Example 8. In Vitro Enzymatic Assays

The metabolic consequences of selective deuteration of tryptamine-basedcompounds were ascertained in two in vitro assays, i.e., monoamineoxidase A (MAO-A) and rat liver microsomes (RLM). Rat liver microsomalassays are considered a good proxy of the in vivo liver metabolismcontrolling the metabolic fate of tryptamines. Similar outcomes ofdeuteration have been detected in the in vitro assay of different animalspecies including human liver microsomes.

Without being bound to any particular theory, it is hypothesized thatthe major metabolic degradation pathway involving tryptamines,especially the exocyclic side chain of tryptamines, is controlled by theMAO-A enzymes. Consequently, for certain molecules, it is believed thatspecific deuteration in the exocyclic moiety of tryptamines (like theN—CH₂ fragment) can make a significant impact on the overall metabolickinetics, i.e., the significant slowing of enzymatic degradation of thetryptamine derivatives discussed herein. In these instances, increasedmetabolic stabilities in both MAO-A and RLM assays were observedrelative to the base nondeuterated compounds. In absence of MAO-Ametabolism, deuteration of the N—CH₂ group had no impact on the RLMdigest kinetics. No metabolism of tryptamines by MAO-B enzyme wasobserved.

Test results are summarized in Table 7 that established a set ofexemplary compounds suitable for selective deuteration of the N—CH₂fragment and also provided additional information regarding selectivedeuteration in other parts of the molecules. Comparison between thecompounds was made using a best-fit curve to calculate half-life, i.e.,a time point where 50% of the compound is digested in the assay.

hrMAO-A (Lot #8213001) and the hrMAO control (Lot #1067001) werepurchased from XenoTech. The reaction mixture was prepared as describedbelow. The co-dosed TAs were added into the reaction mixture at a finalconcentration of 1 microM each. The positive control, kynuramine (25microM), was run simultaneously with the TAs in a separate reaction. Thereaction mixture (without TAs or kynuramine) was equilibrated in ashaking water bath at 37° C. for 5 minutes. The reaction was initiatedby the addition of the TAs or kynuramine, and the mixture was incubatedin a shaking water bath at 37° C. Aliquots (100 microL) of the TAreaction mixture were withdrawn at 0, 5, 10, 20, 30, 60, and 120minutes. Aliquots (100 microL) of the positive control reaction mixturewere withdrawn at 0 and 30 minutes. TA and kynuramine samples wereimmediately combined with 100 microL of ice-cold 100% MeCN containing0.1% formic acid and IS to terminate the reaction. The samples were thenmixed and centrifuged to precipitate proteins. All TA samples wereassayed by LC-HRAMS. The PARR (analyte to IS) at each time point wascompared to the PARR at time 0 to determine the percent remaining ateach time point. Reaction composition: hrMAO 0.02 mg/mL; PotassiumPhosphate, pH 7.4 100 mM; Magnesium Chloride 5 mM; Test Articles (each)1 microM.

Substrates were incubated in 200 μl of medium that consisted of 100 mgrat liver microsomes, NADPH regenerating system (1 mM NADP, 1 unit/ml ofisocitrate dehydrogenase, 5 mM isocitric acid, 5 mM magnesium chloride),and 25 mM of phosphate buffer (pH 7.4). The reaction was terminated atdifferent time points (0, 5, 10, 20, 30, 60, and 120 minutes) by theaddition of 300 μl of acetonitrile. For the analyses of products, theprecipitated salts and proteins were spun out on a centrifuge, theresidual solution diluted with 300 μl of water and injected into theLC/MS (Agilent 1200 system interfaced with an ABS Sciex 4000 QTRAPLC/MS/MS Mass Spectrometer). The metabolic stability was estimated byevaluating the rate of disappearance of the main parent peak.

TABLE 7 Results of in vitro MAO-A and RLM assays R₈ R₉ R₂ R₄ R₅ R₆ R₇X_(1,2) Y_(1,2) MAO, % RLM, % Nor-Tryptamines CH₃ H H  H H H  H  H,H H,H  R R CH₃ H H H H H H D,D D,D 622 189 CH₃ H H H H H H D,D H,H 578 182CD₃ H H H H H H D,D D,D 711 214 CD₃ H H H H H H D,D H,H 744 207 C₂H₅ H HH H H H H,H H,H R R C₂H₅ H H H H H H D,D D,D 140 142 C₂H₅ H H H H H HD,D H,H 145 138 C₂D₅ H H H H H H D,D D,D 166 159 C₂D₅ H H H H H H D,DH,H 170 151 i-C₃H₇  H H H H H H H,H H,H NR R i-C₃H₇ H H H H H H D,D D,DNR [106] i-C₃H₇ D D D D D D H,H H,H NR 145 Allyl H H H H H H H,H H,H NRR 4-OH-Nor-Tryptamines CH₃ H H OH H H H H,H H,H R R CH₃ H H OH H H H D,DD,D 396 160 CH₃ H H OH H H H D,D H,H 395 154 CD₃ H H OH H H H D,D D,D459 173 CD₃ H H OH H H H D,D H,H 466 163 C₂H₅ H H OH H H H H,H H.H NR RC₂H₅ H H OH H H H D,D D.D NR [94] C₂D₅ H H OH H H H D,D D,D NR [93] C₂H₅D D OH D H H H,H H,H NR R i-C₃H₇ H H OH H H H H,H H,H NR R i-C₃H₇ H H OHH H H D,D D,D NR [108] i-C₃H₇ D D OH D D D H,H H,H NR 131 N,N-DialkylTryptamines CH₃ C₂H₅ H H H H H H,H H,H R R CH₃ C₂H₅ H H H H H D,D D,D162 131 CH₃ C₂H₅ H H H H H D,D H,H 168 121 C₂H₅ C₂H₅ H H H H H H,H H,HNR R C₂H₅ C₂H₅ H H H H H D,D D,D NR [105] Allyl Allyl H H H H H H,H H,HNR R Allyl Allyl H H H H H D,D D,D NR [106] i-C₃H₇ i-C₃H₇ H OH H H H H,HH,H NR R i-C₃H₇ i-C₃H₇ H OH H H H D,D D,D NR  [97] i-C₃H₇ i-C₃H₇ D OH DD D H,H H,H NR 167 4-OMe Tryptamines CH₃ CH₃ H OCH3 H H H H,H H,H R RCH₃ CH3 H OCH3 H H H D,D D,D 325 190 CH₃ CH3 H OCH3 H H H D,D H,H 335185 CH₃ C₂H₅ H OCH3 H H H H,H H,H R R CH₃ C₂H₅ H OCH3 H H H D,D H,H 281163 CH₃ C₂H₅ H OCH3 H H H D,D D,D 291 161 C₂H₅ C₂H₅ H OCH3 H H H H,H H,HNR R 5-OH Tryptamines CH₃ CH₃ H H OH H H H,H H,H R R CH₃ CH₃ H H OH H HD,D D,D 418 136 CH₃ CH₃ H H OH H H D,D H,H 415 133 CH₃ C₂H₅ H H OH H HH,H H,H R R CH₃ C₂H₅ H H OH H H D,D H,H 173 132 CH₃ C₂H₅ H H OH H H D,DD,D 179 144 C₂H₅ C₂H₅ H H OH H H H,H H,H NR R C₂H₅ C₂H₅ H H OH H H D,DD,D NR [106] 5-OMe Tryptamines CH₃ CH₃ H H OCH3 H H H,H H,H R R CH₃ CH3H H OCH3 H H D,D H,H 227 185 CH₃ CH3 H H OCH3 H H D,D D,D 229 184 CH₃C₂H₅ H H OCH3 H H H,H H,H R R CH₃ C₂H₅ H H OCH3 H H D,D D,D 132 115 CH₃C₂H₅ H H OCH3 H H D,D H,H 126 117 C₂H₅ C₂H₅ H H OCH H H H,H H,H NR RC₂H₅ C₂H₅ H H OCH3 H H D,D D,D NR  [95] C₂H₅ C₂H₅ D D OCH3 D D H,H H,HNR 172 CD₃ CD₃ H H OCD3 H H D,D D,D 372 299 CD₃ CD₃ H H OCD3 H H D,D H,H366 288 CH₃ CH₃ H H OCD3 H H H,H H,H [109] 151 DMT CH₃ CH₃ D D D D D H,HH,H [103] [106] CH₃ CH₃ D D D D D D,D D,D 551 243 CD₃ CD₃ D D D D D D,DD,D 643 325 half-life differentiation in metabolic assays presented as %vs. the related nondeuterated compounds R means substantiallymetabolized NR means not metabolized at the last assay time point (120min) the values in square brackets are within 10% difference (assay'saccuracy), indicative of no deuteration effect on metabolism

As can be seen in Table 7, there is MAO-A metabolic activity fortryptamine-based substrates having N-Me and N-Et substituents, as wellas the asymmetrically substituted like the N,N-Me,Et substituents,whereas no MAO-A metabolic activity was observed for a tryptamine-basedsubstrate having a N,N-Et moiety. Consequently, tryptamine-basedsubstrates with N,N-Et and higher alkyl chains, e.g., i-Pr and allyl,deuteration in the —N—CH₂—CH₂ and N—R₈,R₉ fragments had no metabolicconsequences observed in both MAO-A and RLM assays. Tetra-deuteration ofthe ethylene bridge or selective bis-deuteration at the alpha carbonstabilized the substrates against MAO-A action compared to the metabolicactivity for their base nondeuterated substrates, i.e., slowed downenzymatic degradation. Deuteration at the N—R₈,R₉ fragment furtherstabilized the substrates against MAO-A action as seen in Table 7.Per-deuterated DMT-d₁₅, with additional deuteration in the phenyl ringprovided no improvement in half-life compared to DMT-d₁₀ selectivelydeuterated at the exocyclic moiety observed in the RLM assay. However,it is observed that phenyl ring deuteration plays a role in slowing downRLM metabolism of the tryptamines that have no MAO-A metabolism. Withoutbeing bound to any particular theory, it is believed that there is acontribution to metabolism of tryptamine-based substrates from enzymesother than MAO like CYP isoforms to generate ring-hydroxylatedmetabolites. Involvement of the CYP enzymes is also believed to beinvolved in slowed RLM metabolism of the -OMe deuterated vs.non-deuterated 5-OMe substituted tryptamines.

All patents, patent applications, and other scientific or technicalwritings referred to anywhere herein are incorporated by referenceherein in their entirety. The embodiments illustratively describedherein suitably can be practiced in the absence of any element orelements, limitation or limitations that are specifically or notspecifically disclosed herein. Thus, for example, in each instanceherein any of the terms “comprising,” “consisting essentially of,” and“consisting of” can be replaced with either of the other two terms,while retaining their ordinary meanings. The terms and expressions whichhave been employed are used as terms of description and not oflimitation, and there is no intention that in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claims. Thus, itshould be understood that although the present methods and compositionshave been specifically disclosed by embodiments and optional features,modifications and variations of the concepts herein disclosed can beresorted to by those skilled in the art, and that such modifications andvariations are considered to be within the scope of the compositions andmethods as defined by the description and the appended claims.

Any single term, single element, single phrase, group of terms, group ofphrases, or group of elements described herein can each be specificallyexcluded from the claims.

Whenever a range is given in the specification, for example, atemperature range, a time range, a composition, or concentration range,all intermediate ranges and subranges, as well as all individual valuesincluded in the ranges given are intended to be included in thedisclosure. It will be understood that any subranges or individualvalues in a range or subrange that are included in the descriptionherein can be excluded from the aspects herein. It will be understoodthat any elements or steps that are included in the description hereincan be excluded from the claimed compositions or methods.

In addition, where features or aspects of the compositions and methodsare described in terms of Markush groups or other grouping ofalternatives, those skilled in the art will recognize that thecompositions and methods are also thereby described in terms of anyindividual member or subgroup of members of the Markush group or othergroup.

Accordingly, the preceding merely illustrates the principles of themethods and compositions. It will be appreciated that those skilled inthe art will be able to devise various arrangements which, although notexplicitly described or shown herein, embody the principles of thedisclosure and are included within its spirit and scope. Furthermore,all examples and conditional language recited herein are principallyintended to aid the reader in understanding the principles of thedisclosure and the concepts contributed by the inventors to furtheringthe art, and are to be construed as being without limitation to suchspecifically recited examples and conditions. Moreover, all statementsherein reciting principles, aspects, and embodiments of the disclosureas well as specific examples thereof, are intended to encompass bothstructural and functional equivalents thereof. Additionally, it isintended that such equivalents include both currently known equivalentsand equivalents developed in the future, i.e., any elements developedthat perform the same function, regardless of structure. The scope ofthe present disclosure, therefore, is not intended to be limited to theexemplary embodiments shown and described herein. Rather, the scope andspirit of present disclosure is embodied by the following.

What is claimed is:
 1. A compound, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
 2. Apharmaceutical composition comprising a compound and a pharmaceuticallyacceptable vehicle; wherein the compound is

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 3.The pharmaceutical composition of claim 2, wherein the compound is

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 4.The pharmaceutical composition of claim 2, wherein the compound is

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 5.The pharmaceutical composition of claim 2, wherein the compound is inthe form of a pharmaceutically acceptable salt.
 6. The pharmaceuticalcomposition of claim 2, which is in a liquid dosage form.
 7. Thepharmaceutical composition of claim 2, which is in a solid dosage form.8. The pharmaceutical composition of claim 2, which is adapted forintravenous administration, subcutaneous administration, orintramuscular administration.
 9. The pharmaceutical composition of claim2, which is adapted for oral administration.
 10. The pharmaceuticalcomposition of claim 2, which is adapted for administration viainhalation.
 11. The pharmaceutical composition of claim 2, which isadapted for nasal administration.